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I want to visualise secondary structures of multiple proteins aligned (something similar to this figure). Any recommendations?
Thanks in advance
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try this one:
all the best
fred
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Why would AlphaFold give a protein model that contains homoserine instead of serine? Is there anything wrong with the predicted structural models? Thank you.
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Hi, how did you get the model? did you input the sequence or you downloaded the sequence from their website. It is unlikely that AFold should give homoserine rather than serine since its training material contains natural sequences.
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Can the differently coloured region around the ligand be saved so that I can directly see the coloured region the next time I open it? If so, what format would be the file? pdb format? Thank you.
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To preserve all the information of a ChimeraX session, you have to save it as a session file (extension .cxs). This enables you to continue the session from exactly the point where you saved it, colouring, orientation and all.
Saving as .pdb would only save the coordinates, no ChimeraX specific information.
You use the .pdb format (or .cif) to transfer the coordinates to other programs which cannot interpret the chimeraX specific information.
See https://www.cgl.ucsf.edu/chimerax/docs/user/commands/save.html to see a listing of all supported formats, and which part of the session they cover - the session file is the only one that covers all the information in your ChimeraX session - but it can only be opened by ChimeraX! All other formats only export the part of the information that can be interpreted by a particular class of other programs, e.g. images, that are 2D views that you can print or insert into a word processing file or a powerpoint presentation.
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I used AlphaFold to predict the structure of a protein that has not been well studied.
I have a pdb file of the predicted structure.
Now I would like to identify the domains of the protein using this pdb file.
Is there a suitable tool for my purpose?
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It depends on how you want to identify domains.
AlphaFold2 uses HMMER(http://hmmer.org/) to search seq DB(Pfam)s, and make alignment files, then based on these alignment files calculate the contact maps for folding. So...
1) aa seq-based domain info:
You can grab it directly from AlphaFold2 after HMMER calculation. However, simply you can put your aa seq into the Pfam website will give a similar result. This kinda method will work only when a similar seq is on the DB. AlphaFold2 does some stupid things when it is given multi-domain protein seq which is not on the Pfam DB.
2) Without having aa seq info, use only the PDB file to predict the domain:
well, this could be a harder question, a) either you write custom python code to calculate the center of mass and define the cutoff value to identify two domains,s or b) use at least two PDB files of the same protein and then align them then calculate the relative deviation of the other. We have a couple of unpublished multi-domain protein structures and compared them with AlphaFold2's performance. it predicted well on domains but not the relative position of each domain.
I think you need to provide more info about why and what is next step or what is the purpose of identifying the domain from AlphaFold2 prediction, if not Pfam domain info?
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Hii, Is there a way I can extract the alternative spliced protein isoform structures from PDB? Also can we mapped the structure to uniprot sequence So we can know which structure belong to which isoform sequence?
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Unfortunately, most of the databases contain 3D structures only for canonical isoforms. But, you would try Google Colab, a phyton-based online notebook running AlphaFold2, which can predict the structure of any custom sequence or noncanonical isoform. Check this out https://youtu.be/le7NatFo8vI
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Is AlphaFold accurate enough when the protein shares less than sequence similarity with the closest, structurally solved homologue?
Besides, how accurate is Alphafold in de novo structure prediction of protein families without solved structures?
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Several studies have found that AlphaFold predicts better structures than other approaches. The EBI alphafold database (alphafold.ebi.ac.uk/faq) displays the per-residue confidence score (pLDDT). It provides information about the model's accuracy. The majority of plant proteins in the EBI AlphaFold DB (alphafold.ebi.ac.uk/search/text/Oryza%20sativa%20subsp.%20japonica) have a pLDDT score of >50. Even proteins with less identity appear to be accurately predicted by the AF. For longer proteins and disordered proteins, AlphaFold has some limitations.
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Hi. Is it always invalid to get the docking result obtained using structures that have not undergone energy minimisation? What would be the factors considered in this decision?
YASARA Structure allows the users to build the missing residues in protein crystal structures using BuildLoop and OptimiseLoop command. If the missing residues are modelled using BuildLoop and OptimiseLoop command only without energy minimisation, is the subsequent docking result valuable and valid. In other word, should the data generated this way should be discarded as invalid?
Alternatively, is it meaningful to retain the docking results generated using the same modelled structures with and without energy minimisation, and hypothesise that the best-ranked peptides obtained in both methods can be one of the best peptide inhibitors, which can only be confirmed experimentally?
Thank you.
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Yes, it is mandatory to determine the proper molecular arrangement in space since the atomic coordinates of the protein structures are not energetically favorable. . The aim of energy Minimization is to find a set of coordinates representing the minimum energy conformation for the given coordinates b/w the amino acids. Lower the energy more stable they are.
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I want to perform targeted molecular docking of:
(a) a receptor (enzyme) whose structure is not availabe, and hence has been built by computational ab intio methods (and not homology, since the % identity is very low);
(b) a substrate whose structure is availabe.
Given that, the active sites of the enzyme are also not truly available, but has been obtained from (a) literature review; or
(b) inferred from cavities/clefts predicted by CASTp results, how exactly should I perform targeted molecular docking?
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Hi. I am currently designing peptide ligands.
I noticed that DUD-E (Directory of Useful Decoys, Enhanced) can be used to generate decoys for small molecules. I wonder if DUD-E is equally useful in generating decoys for the peptide ligand.
Is there other way of decoy generation for peptides?
Thank you.
Sincerely yours,
Thai Leong
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A good decoy would be randomizing the sequence of your query peptide, an construct some of them. This would give you a set of same length peptides with the same aa composition. This is similar to the procedure in BLAST for estimating E-values for alignments
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Dear all, Hope you all doing well.
I was worried about the prediction of protein-protein interaction using online servers like ClusPRO. Actually recently we found that Protein A interact with Protein B using yeast two hybrid method. Protein B exist as a complex with Protein C, D, and E. Now, biochemically, Protein A didn't show interaction with Protein C, D and E. However, when I performed the protein-protein docking using ClusPRO, it shows interaction of Protein A with all Protein C, D and E. The question is how to rely on such online servers. Because it is giving interaction with whatever protein (as receptor and ligand) you feed to the Job server. It doesn't make any sense to me. How one can differentiate in-silico that Protein A and Protein B is the better interaction propensity than other member of the complex. I cannot do Molecular Dynamics simulation for such huge complexes with all permutation and combinations, because have no expertise in it and also it will be computationally very expensive. Please explain and give your valuable suggestions this in a simple manner.
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No personal experience but it seems to me that ClusPro as described in their paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540229/ is one of the best performing programs available (and cited >1000 times). A general rule is to never rely on one (bioinformatics) method. So, I would:
-Use at least one other docking protein and realise that no method is 100% accurate (usually round 90% is the best you can get) and every method has their pros and cons
-Rely on the biochemical evidence (more). However, do realise that the method used might not be flawless or is unable to show subtle differences that might be relevant in your case
-Use another (biochemical/biophysical) experimental method to confirm your earlier experimental findings
Best regards.
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Let's say we docked Protein X with Ligand A, Ligand B and Ligand C respectively.
Meanwhile, we have three different desktops, i.e. Desktops 1-3 for molecular dynamic (MD) simulation. Can we make use of the desktops using the following way in speed up the process of getting the results from MD simulation?
First round of MD simulation:
Desktop 1 - Protein X-Ligand 1 complex
Desktop 2 - Protein X-Ligand 2 complex
Desktop 3 - Protein X-Ligand 3 complex
Second round of MD simulation:
Desktop 1 - Protein X-Ligand 3 complex
Desktop 2 - Protein X-Ligand 1 complex
Desktop 3 - Protein X-Ligand 2 complex
Third round of MD simulation:
Desktop 1 - Protein X-Ligand 2 complex
Desktop 2 - Protein X-Ligand 3 complex
Desktop 3 - Protein X-Ligand 1 complex
Thank you.
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It is okay to do that. The results are supposed to be machine independent, so that peers can also reproduce the results. Make sure that the software version is the same in all three devices.
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Hi,
I have been trying to minimize a protein showing invalid bond type in some residues. while minimizing it throw an error "restrained minimization has failed". please help
thanks in advance.
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You need to have Prime license to run the protein minimization.
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I generated the predicted structure of a dimer of proteins using AlphaFold2, but it has overlapped amino acids like the picture.
Because of this, SMOG ( https://smog-server.org/cgi-bin/GenTopGro.pl ) returns an error `FATAL ERROR: Contact between atoms 356 451 below threshold distance with value 0.192` when using this PDB as an input.
What I came up with was performing energy minimization on the entire protein by MD simulation software like Gromacs or resolving a part of the amino acid sequence using molecular viewers or modeling software like Pymol.
Which is a better way or is there another way to solve this issue?
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I checked your PDB file with both VMD and UCSF chimera. I could not find overlaps or missing .....
Then i checked it with gromacs 5.1.1 and generate a topology file for it ( OPLAS FF)...
Could you please discuss about your exact problem, becuase i think you can minimize your this PDB file with out any problem in Gromacs or VMD or ....
I also checked your PDB file in text format and i could not find any overlap residues,
Please read SMOG help or tutorial for specific instruction of pdb file, hope this help you ....
Please check the attached files
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If MD simulations converges to Boltzmann distributions ρ∼exp(−βϵ) after sufficiently long time why do we need MD simulations, as all the macroscopic quantities can be computed from the Boltzmann distribution itself. This question I am asking for short peptides of sequences of few amino acids.(tripeptide, tetrapeptide etc).
For instance in the given above (link) paper, they are using MD to generate Ramachandran distributions of conformations of pentapeptide at a constant temperature. So this should obey statistical mechanics. If it is so, then this should satisfy Boltzman distributions.So I should be able to write down the distributions using boltzmann weight as follows,
ρ({ϕi,ψi})∼exp(−βV({ϕi,ψi}))
.Here, all set of Ramachandran angle coordinates of the pentapeptides is given by {ϕi,ψi}{ϕi,ψi}.
Why should I run MD to get the same distributions?
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As
Behnam Farid
pointed out, you cannot know all the relationships (the functional form V({ϕi,ψi})) between the different amino acids (sterical clashes, interactions based on charges or hydrophobicity) to predict the energetically favorable combinations of phi and psi and hence need to sample them. The state distribution is affected by the amino acid sequence, may differ with the force fields and simulations methods, does depend on the solvent (ions etc.) and temperature.
Have a look here to see how complex the conformational space of small peptides (13-15) can already be:
Bests
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I'm a non-scientist fascinated by structural biology and trying to understand how structural biologists do molecular replacement, and I would love your help.
I understand that the general rule of thumb for molecular replacement is that you need a search model that shares >20% sequence similarity as your target protein. However, sequence similarity does not always translate into structural similarity, and a search model with low sequence similarity may turn out to be a good model if its 3D structure shares enough similarity with the target protein.
My question is: how do you find such search models with low-sequence identity but high structural similarity for molecular replacement? We do not yet know the structure of the target protein, so I'm having a hard time understanding how you can identify a search model that may share high structural similarity.
For instance, based on the sequence of the target protein, do you use databases like InterPro that predicts which protein family the target protein might fall in and find potential search models from that predicted family?
Thank you!
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To find such low-identity templates, you use threading algorithms: these do not simply compare two sequences, but basically aligns the query sequence to the template structure: https://en.wikipedia.org/wiki/Threading_(protein_sequence) and evaluates how "happy" your query sequence is in the template fold by appropriate energy functions.
"I-TASSER (Iterative Threading ASSEmbly Refinement) is a hierarchical approach to protein structure and function prediction. It first identifies structural templates from the PDB by multiple threading approach LOMETS, with full-length atomic models constructed by iterative template-based fragment assembly simulations. Function insights of the target are then derived by re-threading the 3D models through protein function database BioLiP. I-TASSER (as 'Zhang-Server') was ranked as the No 1 server for protein structure prediction in recent community-wide CASP7, CASP8, CASP9, CASP10, CASP11, CASP12, and CASP13 experiments. It was also ranked as the best for function prediction in CASP9. The server is in active development with the goal to provide the most accurate structural and function predictions using state-of-the-art algorithms.
(Reference: A. Roy et al. 2010. Nature Protocols 5: 725-738)"
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I am working on a ligand that is co-crystalized to parotein, but the ligand is missing some residues that makes it appear as if it was separated into two ligands!
what I need is to connect them into one to run molecular dynamics simulation, what is the best tool to do so, also what are the steps to make sure that it will be mostly accurate?
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Try Ligandscout or Maestro, Schrodinger.
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Hello all
Is there any reliable and free web server that runs molecular dynamics simulation of proteins?
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These days journals demand for 100 ns and Online tools are not reliable for MDS. The best solution for MDS is always gromacs or schrodinger.
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In the PubChem database I could find a 2D structure of the compound (CID 24763) but wants a 3D structure for docking, moreover the compound is too long so is there any technique to cut it short since the compound is starch like polysaccharide??
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Download the 2D and convert into 3D using Marvin sketch or chemsketch or chemdraw.
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I am trying to estimate the width of DNA from its crystal structure.
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Hi can you share the notebook ?
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I've used phyre2 to model the protein for the simulation using Gromacs, but later I found that 2/3 proportion of the structure ( except for IDR ) had been already determined by X-ray crystallography.
The known structure contains Zn2+ to stabilize the structure of the entire protein, so I doubt phyre2 can predict decent structure. How should I model the structure of proteins using a known structure as a part of it?
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Dear community,
As far as I understand, negative density features point at stuff that is in the model, but not supported by experimental data.
However, in many cases (e.g. attached image), when you visualize the densities, there are negative (red) density blobs not containing any atoms inside. Just empty space inside. There is nothing in the model in those regions of space. How it should be interpreted?
Could you tell me please what I am missing?
Would be grateful for any help,
Best wishes,
Aliaksei
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Even in a well-refined structure some residual difference density is always expected. In this case the small negative peak could have to do with imperfect bulk solvent modelling/scaling. I wouldn't worry about it too much, it's very minor in this case. The negative difference density at the carboxylic acid group of the glutamate however could be indicative of radiation damage; in that case refining with lower occupancy can be a solution. Other tell-tale signals for radiation damage are e.g. cleaved Cys-Cys disulfid bonds. HTH, Jonathan.
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I have used modeller to generate a pdb file. i have run it on PROCHECK. but the input format is not compatible. (brook haven format). How do i convert my file? or any other way? Please help. ASAP
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PROCHECK already accepts .pdb files. As far as I understand, Brookhaven might be an alternative way to call the PDB format (an old one, maybe?). I found some references to it around the internet, e.g. "Brookhaven Protein Databank format".
Anyway, just a remark: check to see if protein chains are specified in the MODELLER output file (sometimes MODELLER doesn't set chain IDs; this can cause problems with PROCHECK). If in doubt, don't use the chain parameter in the PROCHECK command, e.g. `procheck model.B99990004.pdb 2.0`. The resolution parameter is necessary, but any number is accepted (I've used 2.0 in the example above).
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While am running the EM, the minimizatin gets stopped before the forces get converged at step 14
Steepest Descents:
Tolerance (Fmax) = 1.00000e+03
Number of steps = 50000
Step= 14, Dmax= 1.2e-06 nm, Epot= 1.84916e+18 Fmax= inf, atom= 7809
Energy minimization has stopped, but the forces havenot converged to the
requested precision Fmax < 1000 (whichmay not be possible for your system).
It stoppedbecause the algorithm tried to make a new step whose sizewas too
small, or there was no change in the energy sincelast step. Either way, we
regard the minimization asconverged to within the available machine
precision,given your starting configuration and EM parameters.
Double precision normally gives you higher accuracy, butthis is often not
needed for preparing to run moleculardynamics.
You might need to increase your constraint accuracy, or turn
off constraints altogether (set constraints = none in mdp file)
writing lowest energy coordinates.
Back Off! I just backed up em.gro to ./#em.gro.9#
Steepest Descents converged to machine precision in 15 steps,
but did not reach the requested Fmax < 1000.
Potential Energy = 1.8491607e+18
Maximum force = inf on atom 7809
Norm of force = inf
What should I do?
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@Richard Mariadasse can you suggest me how do you solve the problem?
I'm having the same issue
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A number of post translational modifications can occur to a protein, including phosphorylation, methylation etc. I am aware that there are a number of servers and tools to predict positions for these modifications based on sequence and/or structural patterns or motifs. However, is there a tool (or server) available that can actually model them on a structure (or a model)?
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Hello,
If you want to add a post translational modification in an existing pdb file You can try Vienna 2.0
Best,
Christophe
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Given:
1. The nearest neighbor of 𝑝𝑖 then 𝑝𝑖-𝑝𝑗 is a Delaunay edge.
2. In a 3D set of points, if we know that consecutive points ie... 𝑝𝑖-𝑝i+1 are nearest neighbors.
3. The 3D points do not form a straight line
Assumption:
Each Delaunay tesselation (3D) has at least 2 nearest neighbor edges.
Is my assumption true? If not can you please explain to me the possible exceptions?
Thanks,
Pranav
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Are you trying to play chess in 3D?
Your idea is a good one, but your assumptions are not.
You need to give a clear definition of paths, so I suggest for you to start in one 3D box, it includes 8 points. I prefer to give each point the following notation
P(i, j, k), so the locations of the 8 points are at
(0,0,0) (1,0,0), (0,1,0), (0,0,1), (1,1,0), (1,0,1),(0,1,1) and (1,1,1).
Study this cube carefully, define each Delanoy edge (axioms of the path), and then add another box, which means 12 points, etc.
If you find the closed formula that allows you to calculate all possible paths from the starting point at the origin to the farthest point at the upper corner of the rectangular box, then you are on the right track.
I wish you good luck.
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I would like draw protein 3-D structure? Can anyone suggest me the best software that I can buy?
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I think for drawing of protein 3-D structure, softwares such as SPDBV and PyMOL are proper.
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Hi everyone,
I need to do MD simulation of wild type and ten variants at 50 ns. I am looking for a low-cost cloud service/ simulation environment. Would you please suggest me any?
Thanks in advance.
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This may be too late to be relevant to your work but here's a recommendation anyway.
For a Simulation environment AND cloud service combo that's least expensive (IMO) I'd recommend going with NAMD on AWS.
Relatively inexpensive and pretty easy to set up (I think they even have an image that you can just purchase without needing to set much up).
Best of luck.
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I had used SUMMA server for structure refinement.
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Hello everybody! Somebody knows an open source software for induced-fit docking? I have to dock ligands on receptor-models which have low sequence identity with the template (13-20%) and I was thinking that an induced fit docking can help me to improve the quality of my models, at least in the binding site.
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Fabrizio Fierro great approach. I am doing something similar. I agree that enrichment factor relative to decoy is a key metric for model evaluation. What are the typical values of enrichment did you end up getting?
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Hi,
Typically, the solvent accessibility of water-soluble protein is computed by using a water molecule with a size of 1.4 Å). For my research work, I need to compute the relative lipid (-CH2 as a probe molecule) accessibility for membrane protein structures through NACCESS program. In this regard, I don't know how to change the solvent parameters in NACCESS.
Is there anyone who can help me with this calculation?
Thank you in advance.
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Yuhong Mao I am not using Mac
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I want to run protein-Ligand simulation where gold atoms are ligand. Gromacs is showing error for that. I tried to use Prodrug server also, but it is not generating coordinates for gold atoms. 
Can anyone help me in this?
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@Martiniano Bello , Thank you very much. I have download the golp.tgz and unzip it to the force field folder in gromacs or the input file folder . But I didn't find the relevant force field after runing the 'gmx pdb2gmx' command. Could you explain how to use the Golp for a greenhand? Thank you.
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I want to compare the active sites of some protein models in quantitative way (their volume or dimensions), Is this option available in the following softwares (MOE, YASARA, Pymol, Chimera) as I have access to them only. If any one had a similar experience with one of these softwares specifically.
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PyMOl is the batter solution for this for the countdown of the volume of the protein active site as I know. Furthermore, the total volume of the drug-protein complex or only protein volume with the unit is accurately counted by the YASARA dynamics suit.
Thanks
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Dear all,
I am a beginner and I have plotted dssp plot using cpptraj for the first time using following script;
trajin md-sim.ncsecstruct 1-263 out dssp.gnu sumout dssp.sum.agr
I wanted to know that what is None in dssp.gnu plot. I have read in amber manual that None is nothing just 0 integer. If it is correct so why cpptraj secstruct script plot None. Can I exclude this from dssp plot. Kindly help me.
[set cbtics {"None", "Para", "Anti", "3-10", "Alpha", "Pi", "Turn", "Bend"} ]
Thanks.
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Hi Saman,
"None" refers to no secondary structure predicted, sometimes referred to as random coil.
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Ignoring a proteins sequence, say I have a predicted contact map plotted from a useful tool like ConKit, it can be quite easy to determine general regions of secondary structural features and if is running paralell or anti-paralell etc etc..
However besides this, does anybody have any good tips for breaking the predicted contact map down further to see regions which could be contacts involving loops or helices-loop contacts? In essence I am seeking some tips for how someone would step-by-step analyse different factors from a predicted contact map.
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I have been analyzing 90-amino-acid fragment of a protein using HSQC and triple-resonance (1H-15N-13C) NMR. I know roughly where arginine, lysine, and tryptophan side-chain peaks lie on the HSQC, but how can I definitely distinguish what is a backbone and what is a side-chain? In addition to the HSQC, I have several 3D experiments (e.g. CBCANH and CACB(CO)NH).
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Arg Nε-Hε and at low pH Arg Nη-Hη and Lys Nζ-Hζ are visible in HSQC but these are aliased/folded peaks. Go for an open Sweep Width (in 15N dimension) HSQC where these peaks will appear at their exact 15N ppm values and you can identify them easily. If you go to the R/K side chains' 15N plane in CBCANH, you will observe CD and CG of R or CE and CD of K. The Trp side-chain usually shifted downfield and appear near the bottom left corner.
Start with the assignment, you will understand which one is the backbone NH because in CBCANH and CACB(CO)NH they will show only the CA and CB (these you have to identify based on their C ppm values). But the side chains will be different.
Best wishes.
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in many insect including Lepidoptera, there are two kind of sperm: Eupyrene and Apyrene. how can we distinguish two kind of sperm in pictures?
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Dear Fatemeh,
besides Lepidoptera the other group with well studied sperm dimorphism are the prosobranch gastropods. My studies of Serpulorbis strongly suggest, that the "atypical" spermatozoa supply (or are) nutrition to the typical spermatozoa (which are the regular, fertile spermatozoa). There might be some similarity in your objects of research.
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I need to find weather a region of a protein that I'm currently working on has a Calcium Binding Domain. The putative region has a similar amino acid profile as an EF domain.
I would like to run the sequence through a tool and get some proper perdition results 
I saw on many journal articles, showing the predicted EF hand domains with  EF hand test results. (Attached image)
Can anyone please suggest me a proper prediction server that I can use :)
Thank You
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Try IonCom (Zhang Lab) for any metal binding prediction.
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what is the best protein design program that can assess the effect of mutation in a globular protein structure? i am looking to change the specificity of a protein. but mostly i am interested to measure the outcomes of the mutation on the protein itself rather than the interaction. and if i want to look into the interaction as well should i use protein design or MD softwares?  
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Pymol software
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3d structure of a protein is made up several secondary structure elements like helices and sheets. How to find the number of these elements in a pdb file?
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You can open your pdb in Chimera, go to Tools - Sequence - Sequence and it will give you the answer
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I had developed a homology modeled protein and identified the cavity of the protein through bioinformatic software. unfortunately, i couldn't calculate the cavity volume in my modeled protein. I want to get some information about the cavity volume and size in modeled protein for de novo drug design. kindly let me know the way to calculate the cavity volume of the homology modeled protein
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Hi Bala,
I should see your question earlier :) Our CASTp Server would solve your problem:
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Can't access CastP(an online tool for surface analysis of protein) from links i've found through google(http://cast.engr.uic.edu/castp/calculation.php, http://sts.bioengr.uic.edu/castp/)
I guess their server is down or i'm trying the wrong URL. Please suggest me any alternative.
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Thanks Jeff! Now we've upgraded CASTp into new 3.0 version, this link is correct and didn't change: http://sts.bioe.uic.edu/castp/
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I would like to understand the reason why proteins show frothing.
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Because proteins are amphiphilic and can act as surfactants in a similiar way detergents do. They can adsorb at air-water interface and lower the surface tension of the solution which allows formation of the foam.
Dawid
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I'm currently trying to get the 3D structure of a set of peptides (ranging from 12 to 20 aminoacids). Subsequently we want to make docking analysis against an enzyme.
Which software do you use for that? How do you refine the structure?
Thanks!
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Such short peptides usually do not assume a single defined structure in solution. The structure of the peptide in the complex is not necessarily the dominant conformation in the ensemble of structures in solution, but induced by the interaction with the binding partner. As a consequence, rigid docking of peptides usually is not possible.
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Hello structural biologists! I am interested in developing an inhibitor to target the assembly of a specific heteromultimeric complex. The complex exists in the cytoplasm of most eukaryotic cells. A crystal structure of the entire complex is available. I am interested in targeting the interaction surface between the two proteins.
The binding surface is comprised of two alpha helices, one from each protein. I am aware that PPIs are considered a particularly tough target for inhibitor development. However, I have an advantage here, as several residues in close proximity are known to be essential for complex formation. In a sense, these residues seem to form a binding pocket, albeit one shared between two proteins.
My goal is to develop a pharmacophore model of this 'binding site' so that I can apply virtual screening to look for compounds that can mask this interaction. I have not found much information on the generation of multi-protein pharmacophores. I would be grateful if someone could point me in the right direction.
Regards,
Patrick
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Go through this article:
Pharmacophore based virtual screening for identification of marine bioactive compounds as inhibitors against Mip protein of Chlamydia trachomatis. February 2016, RSC Advances 6(23):18946-18957
DOI: 10.1039/C5RA24999F
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I'm interested about a monoclonal antibody Rituximab, I've found pdb structure of Fc and Fab regions of this. Is there any too/method that I can use to append these and get the full pdb structure?
Fc fragment: 1L6X
Fab fragment: 2OSL
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Since you got both regions from PDB and the hinge region could be found at the files shown by Honegger, you may use any homology modeling tool (such as modeller) to create a full protein based on these tridimensional structures and the amino-acid sequence of your antibody.
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I need a software to draw chemical structures. I have been using the free trial version of ChemDraw, which has expired.  Now I am looking for an alternate software that can do chemical drawing. I am not looking for any special or advanced features. I just need a software that can  generate good quality images for use in publications? 
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There's a free online version of ChemDraw, which is kinda cool.
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Simulation has been extended till 70 ns, but still there is no sign for my protein to become stable. What could be the reason?
My protein is a monomer with two helices connected with a middle linker region of 3 amino acids.
Kindly throw some light.
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Few notes...
1. RMSD below one Angstrom is not big.
2. If you increase the y-axis upper limit from one to two Angstroms, the RMSD line will appear less noisy, and your conclusion about the (in)stability of the protein may change.
3. If you decrease the number of y-axis ticks from ten to five, the RMSD line will appear less noisy, and your conclusion about the (in)stability of the protein may change.
4. By plotting moving average, you can smooth out most of the noise, and your conclusion about the (in)stability of the protein may change.
5. Calculate RMSD after aligning different parts of the protein to identify which parts contribute most to the total RMSD value.
6. Some twenty years ago people were able to achieve excellent quantitative agreement with commensurable experimental data using structures and energies obtained from 500 ps (yes, picosecond) MD trajectories.
7. MD simulation is most useful if used for sampling of the configurational space near the initial structure---and for this purpose, in most cases, i would say, the shorter the trajectory, the better; rather than running one long MD simulation, it is generally better to run many short MD simulations, starting from different initial conditions---this is also very useful if one wants to assess the uncertainty of the quantitative results.
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I want to calculate the binding affinity of a protein (at a specific site) to its ligand. It is already known which atoms of a protein-ligand complex form bonds. So how can I calculate the binding affinity in this case ?
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Hi Mubasher, may I suggest you taking a look at the web application Kdeep, available free of charge at the PlayMolecule suite (www.playmolecule.org). Convolutional neural networks are used to predict binding affinity (Kd and binding free energy) for a set of docked protein-ligand complexes. Therefore, since you seem to have the binding pose of the ligand, you can input the ligand in its docked pose in SDF format, plus the protein in PDB format and Kdeep will return you a predicted affinity. I hope it is useful for you :)
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input: amino acid sequence
output: potential protein binding partners to sequence
Thanks for taking the time to address my question.
Bre
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Dear BreAnne,
actually, it's highly difficult to predict an interaction between two proteins because, as said Steingrimur, it might be strongly related to the 3D structure.
However, there is case for which it becomes a bit less difficult: when the protein binds to a linear motif. A motif is a short amino acid sequence (of about 3 to 6 residues). In this case, the interaction is mostly driven by the sequence since the motif is unfolded most of the time.
You may find interesting details at the ELM website (http://elm.eu.org/), which stands for Eukaryotic Linear Motif. It's a manually curated database based on literature. You enter a protein sequence and you'll see all the putative motifs bound to it. Then it's also possible to search for a special motif if you already know it.
Best regards
Yves
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I have about 2000 of proteins ligands from Protein Data Bank and a lot of their characteristics like full name, molecular formula, SMILES, etc. I would like to classify them in several broad groups according to their chemical features. Is there any database with such data?
Thank you!
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Hi, Kirill! you can try fingerprints based clustering, e.g. RDkit for python can do this (http://www.rdkit.org/docs/Cookbook.html#clustering-molecules)
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How should I rename the ‘Zn’ as ‘M’ and provide energy coefficients for Zn in Autodock Tools? I have just started with autodock tools. My protein has Zn ion in it. In the tutorial, it says something about Grid macromolecules.
"ADT also determines the types of atoms in the
macromolecule. AutoDock can accommodate up to 7 atom
types in the macromolecule. It uses a standard set with two
customizable types, ‘X’ and ‘M’. If your macromolecule has a
non-standard atom type, ADT will prompt you to set up a
customizable type X or M for it by entering energy parameters.
For example, Zn is not in the standard set. If your
macromolecule has Zn, for AutoDock you have to rename the
‘Zn’ as ‘M’ and provide energy coefficients for Zn. ‘X’ can
be used as a second customizable type. It is not possible to
have more than 7 types in the macromolecule."
I do not know how to rename and give charge to Zn. Every time I try to save the file as .pdbqt, it gives 0.000 to Zn. [WARNING: These atoms have zero charge: Zn].
I tried using a PDB file editor, but I always do something wrong.
If someone could help in this aspect.
Thank you very much in advance.
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Few tricks be needed to carryout successfully completion.
1) Update the AD4_parameter.dat according to your necessary metal
2) Update the AD4.1_bound.dat also according to your necessary metal
3) then copy that two files into your installation folder
4) then during grid generation and docking dpf file generation steps, there at set map types option you should mention the required metal atom types and also there is a option named as other option; there u should mention the newly generated parameter file
5) finally the newly generated 2 files should be kept on your docking directory
Finally docking should successfully run.
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We are trying to join a dsRNA with a peptide using HyperChem. The moment we are trying to invoke the model builder, the double stranded structure just mashes up in a weird mesh like thing. Whenever we are trying to optimize the geometry using steepest descent or conjugate gradient or Newton-Raphson, a lot of Oxygen appears from nowhere (which do not show up in other visualization tools like PyMol or VMD). And when we are trying to join the peptide without doing the geometry optimization (the most unscientific thing I have ever heard of), the connecting bond just becomes a long stretch of line (which it should not be, because there's a permissible limit of bond length, isn't it???)
Can anybody shed any light on how to do this job in HyperChem??? We are open to other softwares also, if required.
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take a look at this video
best,
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I have a list of protein pairs that interact with each other, which was obtained using yeast-two-hybrid.No 3D-structure or other deeper structural information.
My tutor wants me to find out the protein-protein interaction site of these pairs using some bioinformatic tools.
I know nothing about bioinformatics or structures,so is this possible to do? can anyone recommend some good programs that can predict PPI sites?
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Thank you all for your kindly help!
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Dear researcher,
I want to simulate a selenium containing enzyme. But when i processed the selenium containing enzyme using pdb2gmx command so it is showing an error.
"Atom SE46 in residue CYS 597 was not found in rtp entry CYS with 11 atoms while sorting atoms"
please give me any suggestion how i can add the selenium during MDS.
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You should first check the literature to see if this selenocysteine is actually functional. Sometimes the heavy atom derivative of a side chain (e.g. selenomethionine, selenocysteine) is used to simply get better diffraction of crystals, and the actual enzyme has the normal sulfur-containing amino acids. If that's the case, just replace Se by S and proceed as normal.
If it really is a selenocysteine, you will have to parametrize it. To do this, you must follow the prescribed parametrization procedure of the parent force field. This can be quite laborious to do.
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Hi,
We are trying to draw a charged amine structure in HyperChem. We jotted down the structure as usual but it is showing without any charge.
Anybody has any idea about how it can be done???
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You should be careful with such a big system because the degrees of freedom is too high. Optimization process in Gaussian does not do a conformational search. It only does a single point optimization. Therefore, you should be very sure about the initial guess structure (input structure). Before going for QM, you may try conformational search or simulated annealing to generate a good starting structure.
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I have been reading that it is important for decoys (inactive molecules) to have similar physico-chemical properties to their matching ligands but different topology in virtual screening benchmark data sets
Why is it that? Does topology play a big role in discriminating ligands from decoys? 
What is the role for topolgy in protein-ligand interaction? 
Would you mind giving me a hint or recommend me some material that I could read? 
Thank you so much for all the help that can be provided :)
Hugs,
Stellamaris
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Hi Stellamaris, what I read from your question is that you are describing receptor antagonists, or competitors.
Matching the ligand binding site of a receptor relies on designing an antagonist that looks like a ligand (based on topology and computer docking programs), but  does not act as a natural ligand and thus inhibits the receptor.    
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I isolated my protein complex from mammalian cells. Purify it using affinity purification methods. but after running chromatography the concentration became very low to go further structural study. How can I I increase concentration without affecting the protein complex? 
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@Woojong Lee  I already tried Ultrafiltration using amicon filters according to the guideline. Thank you, I will try it again with more concern. 
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MODELLER website's  "difficult tutorial", available at link below, makes mention and use of "mGenThreader" software. Problem is: provided website by tutorial where mGenThreaded should be doesn't has the option to use mGenThreader, neither I've found any website for which I can download it. Instead of it, I've found "GenThreader" and "pGenThreader".
So I ask: Where Can I download mGenThreader? If this is not possible, may I use pGenThreader in place of mGenThreader?
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Dear Inacio, I think mGenThreader and GenThreader are the same thing: you need to create an alignment file as input and you can do it online: http://bioinf.cs.ucl.ac.uk/psipred/ 
if it doesn't work I suggest you to get in touch with the developer of GenThreader  Prof David Jones at UCL ( d.t.jones@ucl.ac.uk) I hope this help
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Dear researcher,
                           I want to dock a small protein in the interface of diamer protein. When i submit the diamer structure in to HADDDOCK server it terminates the jobs and do not produce the result. But when i delete the one chain of diamer and proceed the docking it accept and produce the result.
So question is:
is there any problem in diamer construction. If yes please suggest me how to create the diamer.
is there any problem in docking then how can i resolve it.
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HI Rohit,
There are other servers like Zdock , ,Hex, Cluspro, Gramm-X , as and alternative there is Megadock4.0 , (it does not have a server you would have to install it ). However, I think they still will have the same problem due to the large size of your dimer.
One of the options you may try is to extract the interface of the protein and use that as the protein receptor in the docking. Your next option is to establish a collaboration with one of the groups so they run their programs locally in their clusters, with the whole protein. 
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I am trying to calculate SASA scoring function using dock 6.7. However, I am confused about the interpretation of the score.
I have obtained:
SA_Descriptor Score: 14.15
How could I interpret it? What do highest  scores mean? What do slowest scores mean?
I would really appreciate all the help that can be provided!
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From the Dock 6 documentation:
"SASA_Score:
#percentage of ligand exposed times 100"
So your SASA_Descriptor Score of 14.15 is telling you that just over 14% of the molecule is exposed to ligand (or that just under 86% is buried in the receptor).
Higher scores mean that more of your molecule is sticking out into water.  Lower scores mean that more of the molecule is buried in the protein.  For drug applications, you'll probably want to go with the lowest score when choosing an ideal molecule to pursue.  Natural ligands lying on surface grooves might have very different priorities when deciding on an optimum pose.  So which score is 'best' will depend upon what question you're asking.
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I have a protein which has two chains each contains 422 residues, both chains are identical. I want to model this protein but the target sequence which I have contains more than 850 residues. When I combined the two chain residues as a single chain and aligned them with the target sequence it got aligned with the whole 850 residues target sequence and showed 56% identity. I want to model this two chains template protein into a single chain using my target sequence. How can i do it? Any suggestions?.
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This is embarrassing. I just realized that I never answered your follow-up question. Unfortunately, even if I gave the best possible answer now, it would most likely prove absolutely useless to you. I apologize.
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Is there a way to choose the site where we want to place the grid box using the command line?
When creating the grid parameter file in ADT, in the graphical interface, you go to Grid ---> Grid Box --> Center. Then you have to chose to center the grid box in either: 1) Pick an atom 2) Center on ligand 3) Center on macromolecule 4) On a named atom. Therefore, it is possible to chose to center the grid box in the ligand.
My question is how can you do it (chose the position of the grid box) with the command line? Is there a script that I could use? There is no option in the grid parameter file. I have more than 10000 compounds and it would take me a really big amount of time to do it graphically. Then, I would like to automatate the process. Is there a way that I can do it?
I am going to do rescoring which means that the grid will not be in the same place of the ligand automatically.
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Dear collegues,
I have received an answer from Proffessor Sanner (Michel Sanner), who works at the Scripps Research Institute. 
I hope it can  also be useful for you all:
"I have been  working in a version of AutoDock that supports making receptor side  chain flexible and as part of these software developments I wrote the  AGFR software program.
This command line program allows the compute grids (using AutoGrid4) and supports a range of options for automatically positioning of docking
boxes, including using: a known ligand, or a set of residues in the
receptor, a binding pocket identified by our pocket finding method
AutoSite, etc...
The software is not 100% ready for release yet but if you want to give
it a shot you can download the code from
please look at the Use cases on that web page for examples on how to use  the software. (Be aware though that currently the graphical user  interface AGFRgui is broken) but the command like version should be working.
The .trg file contains is a zip file that contains all the maps generated by AutoGrid4 and that can be used for AutoDock4.
So you have to unzip the .trg file and give AutoDock4 the the .map files located in the folder created by unzip.
> unzip myfile.trg
Archive: myfile.trg
inflating myfile/rigidReceptor.C.map
inflating .. "
Thank you all for your help! I really appreciate it!
Huge hugs 
Stellamaris
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I have been a little concerned that the 7H9 media for growing mycobacteria becomes cloudy and crashes out of solution after autoclaving. It is fully dissolved before autoclaving and is clear, but once it has been autoclaved a sandy precipitate accumulates at the bottom of the bottle. Is this a standard problem? Is there anything we can do?
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Hello,
I have experienced this as well.  You indicated that your solution was fully clear before autoclaving, I usually heat it to boiling to be extra careful because if it is not completely dissolved it will present with results like what you are seeing.  I also experienced an issue where my solution was being autoclaved for 30 minute liquid cycle instead of 15 minute liquid cycle, this caused a similar situation as well. I believe it ended up having to do with the glycerol content of the media being very sensitive to extended heat exposure.  Once I corrected these two problems I had not more precipitate at the bottom of my solution after autoclaving.  If the precipitate is of a brown color, which I am assuming based on your 'sandy' description, I would assume something is actually burning or denaturing in the autoclave and double check the things I listed above.  I purchase my 7H9 from Hardy Diagnostics and I have on a couple occasions received sub-par supplies from them so, it also may not be anything you are doing.
Best
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I've isolated a new drug and would like to see the effect on the murine of S. aureus using Autodock
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I would suggest you to target, cell wall synthesizing protein. 
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For example, it is known that one protein is destroyed in ubiquitin-proteasome system, but the E3 ubiquitin-ligase that performes ubiqutilation of this protein is unknown. How can I predict which E3-ligase ubiqutilates this protein? I can find aminoacid sequence of the protein, I know sites for ubiqutilation in this sequence, I can find also information about secondary and tertiary structure of the protein.
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There several ubiquitin-related databases out there, and the most comprehensive one I know is https:/www.omicstools.com.  It has at least nine tools for use in querying about ubiquitin:
UbiNet:
Offers users an effective platform to efficiently study protein ubiquitylation networks among large-scale ubiquitylation data. The current version of UbiNet was designed specifically for humans to…
E3Net:
Provides a comprehensive collection of available E3-substrate specificities and a systematic framework for the analysis of E3-mediated regulatory networks of diverse cellular functions. Currently,…
mUbiSiDa:
mammalian Ubiquitination Site Database; Provides a scientific community with a comprehensive, freely and high-quality accessible resource of mammalian protein ubiquitination sites. The mUbiSiDa was designed to be a widely used tool for…
PlantsUBQ:
Describes the network of Arabidopsis proteins responsible for the covalent attachment of ubiquitin (Ub).  PlantsUBQ provides comprehensive information on the role of this post-translational…
hUbiquitome:
A public resource for the retrieval of experimentally verified human ubiquitination enzymes and substrates. hUbiquitome is the first comprehensive database of human ubiquitination cascades.…
plantsUPS:
A database of higher plants' ubiquitin 26S/proteasome system (UPS). Both automated search and manual curation were performed in identifying candidate genes. Extensive annotations referring to…
UUCD:
Ubiquitin and Ubiquitin-like Conjugation Database; A family-based database for ubiquitin and ubiquitin-like conjugation, which is one of the most important post-translational modifications responsible for regulating a variety of cellular processes,…
UbiProt:
A knowledge base of ubiquitylated proteins. UbiProt contains retrievable information about overall characteristics of a particular protein, ubiquitylation features, related ubiquitylation and…
SCUD:
Saccharomyces Cerevisiae Ubiquitination Database; A web-based database for the ubiquitination system in Saccharomyces cerevisiae (Baker's yeast). SCUD aims to represent a comprehensive yeast ubiquitination system, and is easily expandable with…
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Hi all,
I am learning a lot of things about the computational biology for the first time. I was curious, with the current technology, what is  the possible simulation time range for a research in computational biology using commercial force fields such as AMBER, GROMACS, CHARMM etc? Can we go more than ns without harming the results? 
Thanks!
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What is "possible" is limited only by the quality of the hardware and software (and how much patience you have for waiting on the results). Modern simulations often go well into the microsecond range pretty easily.
The better question is what is necessary to answer the question(s) at hand, and sampling is a general concern. A single, microsecond-length simulation may be less valuable than, say, 10 x 100-ns simulations, but of course that again depends on the purpose(s) of the simulation. Long simulations have exposed the fact that conformations often get trapped in local minima for long periods of time. This can be circumvented with enhanced sampling techniques or by simply running many more simulations from different starting conformations and/or initial (random) velocities.
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I am doing some researches about the 3D structure and binding site of DHFR, I wanted to have any 3D model for BH2 binding with DHFR. I could just find some models for TH2, but not for BH2.
Could some one provide me any model, or paper where I can find such modeling? it is not bad if there were any clear modeling for TH2 as well.
Thanks in advance!
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PDB codes 1DR1, 1DR3, 1DR4, 1DR6 in th eprotein data bank (rcsb.org) is what you are looking for. Relevant publication is:
Crystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin.
McTigue, M.A., Davies 2nd., J.F., Kaufman, B.T., Kraut, J.
(1992) Biochemistry 31: 7264-7273
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Hi!
I was wondering if you can suggest program/script for linux or not, that can calculate the interactions between Ligand and protein from a pdb file. When I'm saying interactions i mean, h-bonds, aromatic interactions, hydrophobic bonds etc.
I found IChem on the internet, but it seems that it doesn't work properly. I couldn't even run it.
Thanks
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The Protein-Ligand-Interaction Profiler https://projects.biotec.tu-dresden.de/plip-web/plip/ adds some details that are not covered by HBplus. Besides the Eeb interface, a command-line driven version is available for download.
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Dear CHARMMers,
can anyone tell me what's the issue?
I try to run calculations with charmm for homology protein file, and when it comes to reading psf file (generated with par_app36_prot.prm file), the error occurs:
"Atom 1 0 NH3 problem in psf
***** LEVEL -3 WARNING FROM <psf_read_formatted> *****
***** atom type not found for atom"
Anyone might help to handle it?
Kind regards
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I noticed that you have 19 Atoms in topology file (psf) for the first residue, but in the PDB file you have 18 atoms. There should be the same number, are they both created in CHARMM?
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for protiens
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When you try to chose which software to use for running MD simulations, there are a few criteria that you may prioritize, such as:
1) possibility of modeling different biomolecular systems (e.g., protein, membranes, DNA, RNA and their complexes);
2) possibility on modeling the solvent environment explicitly and/or implicitly (water, ions, etc,);
3) flexibility on using different force fields for parametrization of the systems and efficient treatment of long-range electrostatic interactions;
4) computation efficiency (in terms of speed) for running long time dynamics (e.g., is the code parallelized, can you use GPU, etc,);
5) possibility on running the simulations in different statistical ensembles (e.g., NVT, NPT) and possibility of using different periodic boundary conditions based on the geometry of the simulation box;
6) implementation of stable numerical integrator methods for solving equations of motion;
7) being easy on building up equilibration protocols (e.g., through documentation and tutorials);
8) providing tools and/or modules for analyzing the trajectories;
9) being able to create outputs in a format which can be easy read from other data visualization and/or analyzing software;
10) being able to read and manipulate the inputs structures (e.g., PDB format files);
11) in some cases, being able to compute complex thermodynamic properties, such as free energies, using advanced molecular dynamics methods;
12) implementation of efficient conformation sampling algorithms;
13) and maybe others (depending on the problem).
Some molecular dynamics engines that satisfy the above mentioned criteria include CHARMM, GROMACS, NAMD, AMBER, DESMOND, TINKER, DL_POLY, and maybe others.
I hope that this helps this discussion!
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molecular docking
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thank you madhusudan
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Hi.. I have DNA solutions annealed. I wanna know the effect of pH on the stability of structures with PBS solution. Answers are appreciated. Thanks!!
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Measure the effect of temperature on the UV absorbance of the DNA at different pHs. As the DNA denatures with heating, the UV absorbance increases. This effect is used to measure the melting temperature of the DNA. The equipment required for this experiment is a spectrophotometer with a thermostatted cuvette chamber.
Another way to do the melting experiment is to use a differential scanning calorimeter, which measures the heat absorbed as the DNA melts during heating.
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What is the basic theory of peak shift (Blue or Red) in circular dichroism spectrum of proteins (208,222 nm of alfa-helix or 218nm of betta sheet). and what is the mean of this blue/red shifts? Could scattering lead to any shift in CD spectrum !?
As it is appear in attached figure, all spectrums belongs to a whole alpha-helix protein, but in different condition. in Uv-vis spectroscopy we could interpret the reason of any shift according to chemical environments and its effects on energy level of molecular orbitals n,pi,pi*. Now  I need to know the theory/reason of any shift in CD. Is it similar to UV-vis?  
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Please see
Decreasing intensity and broadening of both the positive and the negative CD bands leads to a shift in the x-axis intersection point towards higher wavelengths, and both bands also exhibit a slight red shift. These changes can be attributed to absorption flattening and differential scattering phenomena. Absorption flattening is a consequence of the non-random distribution of chromophores within the sample, i.e. to differential absorption from different portions of the sample. In peptide-membrane samples it occurs when the peptide chromophores are sequestered in discrete regions of the sample with high local density. The extent of absorption flattening is proportional to the concentration of absorbers in each particle [43]. Thus, with increasing binding, more and more peptides seem to form extended β-pleated aggregates on the bilayer and thereby enhance the absorption flattening effects in the CD spectrum. Differential scattering of the incident radiation becomes more and more important with increasing aggregate size [44]. Thus, the more extended the β-sheets, the more severe is the loss in spectral intensity.
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In my pdb file, there are 6 chain identifier. How can i select 2 identifier using vmd or pymol? then i will do md simulation. I want to take B and F identifier and will run for md simulaiton. I have attached my pdf file. can anyone help me about it ?