Journal of biomolecular Structure & Dynamics (J BIOMOL STRUCT DYN )

Description

The Journal of Biomolecular Structure and Dynamics cordially welcomes manuscripts from active investigators in biological structure, dynamics, interactions and expression. The Journal will cover both experimental and theoretical investigations in the area of nucleic acids, nucleotides, proteins, peptides, membranes, polysaccharides and all their components, metal complexes and model systems. The Journal publishes original articles, communications a la express and timely reviews.

Impact factor 2.98

  • Hide impact factor history
     
    Impact factor
  • 5-year impact
    1.15
  • Cited half-life
    0.00
  • Immediacy index
    0.25
  • Eigenfactor
    0.00
  • Article influence
    0.32
  • Website
    Journal of Biomolecular Structure & Dynamics website
  • Other titles
    Journal of biomolecular structure & dynamics, Journal of biomolecular structure and dynamics
  • ISSN
    1538-0254
  • OCLC
    9688706
  • Material type
    Periodical, Internet resource
  • Document type
    Journal / Magazine / Newspaper, Internet Resource

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Abstract Listeria monocytogenes, a Gram positive opportunistic food borne pathogen, naturally resistant to many antibiotics and acquired resistance may be a concern in the nearer future. Hence, there is a scope for screening of novel therapeutic agents and drug targets, towards the treatment of fatal listerial infections. The SecA homologs, SecA1 and SecA2 are essential components of the general secretion (Sec) pathway, a specialized protein export system present in Listeria monocytogenes. This study evaluates the use of botanicals against Listeria monocytogenes MTCC 1143 by considering SecA proteins as probable drug targets by high throughput screening approaches. The 3D structure of SecA proteins with good stereo-chemical validity was generated by comparative modelling. The drug likeliness and pharmacokinetic properties of 97 phytoligands identified through extensive literature survey were predicted for drug likeliness and ADMET properties. The inhibitory properties of best candidates were studied by molecular docking. The effect of the selected candidate molecules were further analysed in vitro well diffusion and cell aggregation assays. The antibiotic sensitivity profiling applied to Listeria monocytogens MTCC 1143 using clinically relevant antibiotics showed that the bacteria became drug resistant to many tested antibiotics. The virtual screening suggested that 0.05M cinnamic aldehyde from Cinnamomum camphora and 1, 2-Epoxycyclododecane from Cassia auriculata were identified as potential SecA inhibitors. The well diffusion assays suggested that the selected herbal substances have antibacterial activities. Further, preliminary validation suggested that incorporation of cinnamic aldehyde and methanolic or ethyl acetate extract of Cassia auriculata in broth medium shows growth reduction, misassembly and cell aggregation. This indicates the inhibition of SecA targets.
    Journal of biomolecular Structure & Dynamics 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Helicobacter pylori is a gastric mucosal pathogen and is associated with diseases like peptic ulcer and gastric cancer. To combat H. pylori infection, there is an urgent need for new class of antibiotics due to the emergence of drug-resistant strains. Enzymes involved in bacterial lysine biosynthetic pathways may be potential targets for antibacterial drug development, since lysine is an essential component of the bacterial peptidoglycan cell wall. No pathway exists for lysine biosynthesis in humans; hence, the inhibitors targeting bacterial enzymes may have selective toxicity. dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a critical enzyme of this pathway and deletion of DapE gene is lethal to H. pylori, since the organism has no alternative pathway for lysine biosynthesis. In this study, we reported a 3D model structure of H. pylorie DapE, which consisted of a catalytic domain and a dimerization domain generated by MODELLER software. We also confirmed the stability of the modeled structure through 10 ns molecular dynamics simulation using GROMACS software. Next, to identify potential small molecule inhibitors of DapE, drug-like small molecule-screening library was generated. This was performed by Tanimoto-based similarity searching in the PubChem Database with DapE substrate L,L-SDAP as a query molecule, followed by fragment-based docking approach using GLIDE XP. This approach identified two potential substrate-competitive small molecule inhibitors of DapE. These new molecules may provide a starting point to search for novel therapeutics.
    Journal of biomolecular Structure & Dynamics 09/2014;
  • Journal of biomolecular Structure & Dynamics 09/2014; 5:1-18.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract TSPY (Testis-specific protein, Y-encoded) binds to eukaryotic translation elongation factor 1 alpha (eEF1A) at its SET/NAP domain that is essential for the elongation during protein synthesis implicated with normal spermatogenesis. The eEF1A exists in two forms, eEF1A1 (alpha 1) and eEF1A2 (alpha 2), encoded by separate loci. Despite critical interplay of the TSPY and eEF1A proteins, literature remained silent on the residues playing significant roles during such interactions. We deduced 3D structures of TSPY and eEF1A variants by comparative modelling (Modeller 9.13) and assessed protein-protein interactions employing HADDOCK docking. Pairwise alignment using EMBOSS Needle for eEF1A1 and eEF1A2 proteins revealed high degree (~92%) of homology. Efficient binding of TSPY with eEF1A2 as compared to eEF1A1 was observed, in spite of the occurrence of significant structural similarities between the two variants. We also detected strong interactions of domain III followed by domains II and I of both eEF1A variants with TSPY. In the process, seven interacting residues of TSPY's NAP domain namely, Asp 175, Glu 176, Asp 179, Tyr 183, Asp 240, Glu 244 and Tyr 246 common to both eEF1A variants were detected. Additionally, six lysine residues observed in eEF1A2 suggest their possible role in TSPY-eEF1A2 complex formation essential for germ cell development and spermatogenesis. Thus, more efficient binding of TSPY with eEF1A2 as compared to that of eEF1A1 established autonomous functioning of these two variants. Studies on mutated protein following similar approach would uncover the causative obstruction, between the interacting partners leading to deeper understanding on the structure-function relationship.
    Journal of biomolecular Structure & Dynamics 08/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Post-translational modifications on the tails of core and linker histones dictate transcription and have vital roles in disease and development. Acetylation and deacetylation events enabled by histone acetyl transferases and histone deacetylases (HDACs) on the chromatin milieu are intricately involved in gene regulation. Inhibition of HDACs is emerging as a powerful strategy in regenerative therapy, transplantation, development and in nuclear reprogramming events. Valproic acid (VPA), belonging to the short-chain fatty acid group of HDAC inhibitors, modulates the epigenome altering gene expression profiles across cell lines. This work attempts to explore the methylation profiles triggered by VPA treatment on human embryonic kidney cells (HEK 293) through a biochemical and computational approach. VPA treatment (for 48 h) has been observed to hypermethylate lysine 4 on the core histone H3 and confers a hypomethylation status of H3 lysine 27 in HEK 293 cells leaving the nuclear area and nuclear contour unaltered. Our structural docking and Binding Free Energy (BFE) calculations establish an active role for VPA in inhibiting the demethylase JARID1A (Jumonji, AT Rich Interactive Domain 1A) and the methyl-transferase EZH2 (Enhancer of Zeste Homologue 2). This work has also proven that VPA can inhibit the activity of proteins like GSK3β and PKCβII involved in developmental disorders. This work establishes a dynamic correlation between histone methylation events and HDAC inhibition and may define newer epigenetic strategies for treating neurodevelopmental and oncological disorders.
    Journal of biomolecular Structure & Dynamics 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: In most of the pathogenic organisms including Plasmodium falciparum, isoprenoids are synthesized via MEP (MethylErythritol 4-Phosphate) pathway. LytB is the last enzyme of this pathway which catalyzes the conversion of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Since the MEP pathway is not used by humans, it represents an attractive target for the development of new anti-malarial compounds or inhibitors. Here a systematic in silico study has been conducted to get an insight into the structure of Plasmodium lytB as well as its affinities towards different inhibitors. We used comparative modeling technique to predict the three-dimensional (3D) structure of Plasmodium LytB taking Escherichia coli LytB protein (PDB ID: 3KE8) as template and the model was subsequently refined through molecular dynamics (MD) simulation. A large ligand data-set containing diphospate group was subjected for virtual screening against the target using GOLD 5.2 program. Considering the mode of binding and affinities, 17 leads were selected on basis of binding energies in comparison to its substrate HMBPP (Gold.Chemscore.DG: -20.9734 kcal/mol). Among them, five were discarded because of their inhibitory activity towards other human enzymes. The rest 12 potential leads carry all the properties of any "drug like" molecule and the knowledge of Plasmodium LytB-inhibitory mechanism which can provide valuable support for the anti-malarial-inhibitor design in future.
    Journal of biomolecular Structure & Dynamics 07/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Because intrinsically disordered proteins are incapable of forming unique tertiary structures in isolation, their interaction with partner structures enables them to play important roles in many different biological functions. Therefore, such proteins are usually multifunctional, and their ability to perform their major function, as well as accessory functions, depends on the characteristics of a given interaction. The present paper demonstrates, using predictions from two programs, that the transmembrane proteoglycans syndecans are natively disordered because of their diverse functions and large number of interaction partners. Syndecans perform multiple functions during development, damage repair, tumor growth, angiogenesis, and neurogenesis. By mediating the binding of a large number of extracellular ligands to their receptors, these proteoglycans trigger a cascade of reactions that subsequently regulate various cell processes: cytoskeleton formation, proliferation, differentiation, adhesion, and migration. The occurrences of 20 amino acids in syndecans 1-4 from 25 animals were compared with those in 17 animal proteomes. Gly + Ala, Thr, Glu, and Pro were observed to predominate in the syndecans, contributing to the lack of an ordered structure. In contrast, there were many fewer amino acids in syndecans that promote an ordered structure, such as Cys, Trp, Asn, and His. In addition, a region rich in Asp has been identified between two heparan sulfate-binding sites in the ectodomains, and a region rich in Lys has been identified in the conserved C1 site of the cytoplasmic domain. These particular regions play an essential role in the various functions of syndecans due to their lack of structure.
    Journal of biomolecular Structure & Dynamics 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-à-vis the standard 3D-QSAR methods CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE. These interactions were quantified to gauge the magnitude of their contribution to the biological activity. In order to validate the CoRIA model, a pharmacophore map was first constructed and then used to virtually screen public databases, from which novel scaffolds were cherry picked that were not present in the training set. The biological activities of these novel molecules were then predicted by the CoRIA, CoMFA and CoMSIA models. The hits identified were purchased and their biological activities measured by the Ellman's method for AChE inhibition. The predicted activities are in unison with the experimentally measured biological activities.
    Journal of biomolecular Structure & Dynamics 06/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aspartate β-semialdehyde dehydrogenase (ASADH) is a key enzyme for the biosynthesis of essential amino acids and several important metabolites in microbes. Inhibition of ASADH enzyme is a promising drug target strategy against Mycobacterium tuberculosis (Mtb). In this work, in silico approach was used to identify potent inhibitors of Mtb-ASADH. Aspartyl β-difluorophosphonate (β-AFP), a known lead compound, was used to understand the molecular recognition interactions (using molecular docking and molecular dynamics analysis). This analysis helped in validating the computational protocol and established the participation of Arg99, Glu224, Cys130, Arg249 and His256 amino acids as the key amino acids in stabilizing ligand-enzyme interactions for effective binding, an essential feature is H-bonding interactions with the two arginyl residues at the two ends of the ligand. Best binding conformation of β-AFP was selected as a template for shape-based virtual screening (ZINC and NCI databases) to identify compounds that competitively inhibit the Mtb-ASADH. The top rank hits were further subjected to ADME and toxicity filters. Final filter was based on molecular docking analysis. Each screened molecule carry the characteristics highly electronegative groups on both sides separated by an average distance of 6 Å. Finally, best predicted 20 compounds exhibited minimum three H-bonding interactions with Arg99 and Arg249. These identified hits can be further used for designing the more potent inhibitors against ASADH family. MD simulations were also performed on two selected compounds (NSC4862 and ZINC02534243) for further validation. During the MD simulations, both compounds showed same H-bonding interactions and remains bound to key active residues of Mtb-ASADH.
    Journal of biomolecular Structure & Dynamics 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Mcl-1 has emerged as a potential therapeutic target in the treatment of several malignancies. Peptides representing BH3 region of pro-apoptotic proteins have been shown to bind the hydrophobic cleft of anti-apoptotic Mcl-1 and this segment is responsible for modulating the apoptotic pathways in living cells. Understanding the molecular basis of protein-peptide interaction is required to develop potent inhibitors specific for Mcl-1. Molecular dynamics (MD) simulations were performed for Mcl-1 in complex with three different BH3 peptides derived from Mcl-1, Bax, and Bim. Accordingly, the calculated binding free energies by using MM-PBSA method are obtained and comparison with the experimental determined binding free energies is made. The interactions involving two conserved charged residues (Aspi, and Arg/Lysi-4) and three upstream conserved hydrophobic residues (Leui-5, Ile/Vali-2, and Glyi-1, respectively) of BH3 peptides play the important roles in the structural stability of the complexes. The calculated results exhibit that the interactions of Bim BH3 peptides to Mcl-1 is stronger than the complex with Bax 19BH3 peptides. The hydrophobic residues (position i-9, i-8 and i+2) of BH3 peptides can be involved in their inhibitory specificity. The calculated results can be used for designing more effective MCL-1 inhibitors.
    Journal of biomolecular Structure & Dynamics 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Resistance to antibiotics in bacteria, is one of the major problems of mankind. Each year, a large number of patients due to infection, lose their lives. One of the main mechanisms of antibiotic resistance, is beta-lactamase secretion. This enzyme, hydrolyzes the amide bond of a lactam ring in beta-lactam antibiotics. Bacillus licheniformis is a mesophilic gram-positive bacterium, Which has a high potential to produce beta-lactamase class A. in this study, the inhibitory effects of some malate analogous were studies by in vitro and in vivo studies. In addition, The effects of inhibitor binding on beta-lactamase were studied using MD simulations. Our results showed that diethyl malate and 1-methyl malate can decrease the MIC value of benzyl penicillin by 16 and 8 fold, respectively. Data derived from in vitro studies revealed that decreasing in MIC values is correlated with bata-lactamase inhibition. Molecular docking studies predicted the binding mode of inhibitors with the beta-lactamase active site. The structural analysis from MD simulations exhibits that binding of citrate and diethyl malate cause earlier equilibrium of beta-lactamase. After binding, the fluctuation of Ser 70 is also decreased. Based on our data, diethyl malate can be used to design the potent inhibitor against beta-lactamase class A.
    Journal of biomolecular Structure & Dynamics 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Adverse side effects of drugs are often caused by the interaction of drug molecules to targets other than the intended ones. In this study, we investigated the off-target interactions of some commercially available drugs with human α-thrombin. The drugs used in the study were selected from Super Drug Database based on the structural similarity to a known thrombin inhibitor argatroban. Interactions of these drugs with thrombin were initially checked by in-silico docking studies and then confirmed by thrombin inhibition assay using a fluorescence microplate based method. Results show that the three commonly used drugs piperacillin (anti-bacterial), azlocillin (anti-bacterial) and metolazone (anti-hypertensive and diuretic) have thrombin inhibitory activity almost similar to that of argatroban. The Ki values of piperacillin, azlocillin and metolazone with thrombin are 0.55 nM, 0.95 nM and 0.62 nM respectively. The IC50 values of piperacillin, azlocillin and metolazone with thrombin are 1.7 nM, 2.9 nM and 1.92 nM respectively. This thrombin inhibitory activity might be a reason for the observed side effects of these drugs related to blood coagulation and other thrombin activities. Furthermore, these compounds (drugs) may be used as anti-coagulants as such or with structural modifications.
    Journal of biomolecular Structure & Dynamics 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer's disease led to development of AChE inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime dipeptides binding along with π-π interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore -10.801 and MM-GBSA free energy -34.89 kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin-serine adduct has been investigated by the DFT approach at the vacuum MO6/6-311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH.
    Journal of biomolecular Structure & Dynamics 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Hen egg white lysozyme (HEWL) adopts a molten globule like state at high pH (~12.75) and is found to form amyloid fibrils at alkaline pH. Here, we report that Cu(II) inhibits self-association of hen egg white lysozyme (HEWL) at pH 12.75 both at 37 °C and 65 °C. A significant reduction in Thioflavin T (ThT) fluorescence intensity, attenuation in β-sheet content, reduction in hydrophobic exposure were observed with increasing Cu(II) stoichiometry. Electron paramagnetic resonance (EPR) spectroscopy suggests a 4N type of coordination pattern around Cu(II) during fibrillation. Cu(II) is also capable of altering the cytotoxicity of the proteinaceous aggregates. Fibrillar species of diverse morphology were found in the absence of Cu(II) with the generation of amorphous aggregates in the presence of Cu(II), that are more toxic compared to the fibrils alone.
    Journal of biomolecular Structure & Dynamics 05/2014;