Diego Prada-Gracia- PhD
- Research Group Leader at Hospital Infantil de México Federico Gómez
Diego Prada-Gracia
- PhD
- Research Group Leader at Hospital Infantil de México Federico Gómez
About
70
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Introduction
Current institution
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November 2015 - November 2016
October 2010 - October 2014
Publications
Publications (70)
Cell-penetrating peptides (CPPs) are a diverse group of peptides, typically composed of 4 to 40 amino acids, known for their unique ability to transport a wide range of substances—such as small molecules, plasmid DNA, small interfering RNA, proteins, viruses, and nanoparticles—across cellular membranes while preserving the integrity of the cargo. C...
Cell-penetrating peptides (CPPs) offer a unique and efficient mechanism for delivering therapeutic agents directly into cancer cells. These peptides can traverse cellular membranes, overcoming one of the critical barriers in drug delivery systems. In this review, we explore recent advancements in the application of CPPs for cancer treatment, focusi...
Background:
Opitz GBBB syndrome (GBBB) is an X-linked disease characterized by midline defects, including congenital heart defects. We present our diagnostic approach to the identification of GBBB in a consanguineous family in which two males siblings were concordant for a total anomalous connection of pulmonary veins and minor facial dysmorphias....
In addition to playing a central role in the mitochondria as the main producer of ATP, FOF1-ATP synthase performs diverse key regulatory functions in the cell membrane. Its malfunction has been linked to a growing number of human diseases, including hypertension, atherosclerosis, cancer, and some neurodegenerative, autoimmune, and aging diseases. F...
Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the d...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Hematologic malignancies such as leukemias and lymphomas are among the leading causes of pediatric cancer death worldwide, and although survival rates have improved with conventional treatments, the development of drug-resistant cancer cells may lead to patient relapse and limited possibilities of a cure. Drug-resistant cancer cells in these hemato...
Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the d...
In this work, we studied the mechanisms of classical activation and inactivation of signal transduction by the histamine H3 receptor, a 7-helix transmembrane bundle G-Protein Coupled Receptor through long-time-scale atomistic molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zw...
The survival of patients with non-Hodgkin's lymphoma (NHL) has substantially improved with current treatments. Nevertheless, the appearance of drug-resistant cancer cells leads to patient relapse. It is therefore necessary to find new antitumor therapies that can completely eradicate transformed cells. Chemotherapy-resistant cancer cells are charac...
In this work, we study the mechanisms of classical activation and inactivation of signal transduction by the histamine H3 receptor, a 7-helix transmembrane bundle G-Protein Coupled Receptor through long-time-scale molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zwitterionic p...
Glucose-6-phosphate dehydrogenase (G6PD) is the first enzyme in the pentose phosphate pathway and is highly relevant in the metabolism of Giardia lamblia. Previous reports suggested that the G6PD gene is fused with the 6-phosphogluconolactonase (6PGL) gene (6pgl). Therefore, in this work, we decided to characterize the fused G6PD-6PGL protein in Gi...
The deficiency of glucose‑6‑phosphate dehydrogenase (G6PD) is one of the most common inborn errors of metabolism worldwide. This congenital disorder generally results from mutations that are spread throughout the entire gene of G6PD. Three single-point mutations for G6PD have been reported in the Mexican population and named Veracruz (Arg365His), G...
Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-en...
The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by physically interacting with t...
Lipid distributions of A) PA, B) PI, C) PIP1-3, D) PS, and E) GM around individual protomers during the final 2 μs of the low receptor density simulations with the BB beads of the receptors fixed. The dots indicate the centers of mass of the BB beads of the receptor helices.
(PDF)
Plots showing the average lipid order (left) and bilayer thickness (right) for one high receptor density simulation run of a mixed array of inactive and active MOR during which time the BB beads of the receptors were fixed.
The data is averaged over all lipids, excluding the ones that flip-flop across the membrane (i.e. CHOL, CER, and DAG). For the...
Structure of A) a cholesterol, B) a PC/SM lipid, and C) a GM lipid with the ROH, GL1, and AM1 beads used in the lipid analysis colored in cyan. The headgroup beads are in pink and the remaining tail beads in grey.
(PDF)
The fraction of lipids with each headgroup in the plasma membrane at the start of all of the simulations.
‘Other’ in the upper leaflet includes: CER (0.7%), LPC (1.0%), and DAG (0.4%). ‘Other’ in the lower leaflet includes: PA (1.5%), PIP1-3 (1.6%), CER (0.1%), and DAG (0.5%). The total number of lipids in the upper and lower leaflets was approxima...
The bilayer thickness (nm, top row) and lipid order (bottom row) of the non-flipping lipids within 3.125 nm of the protein center of mass calculated as a function of the helix index during the last 2 μs of membrane equilibration of the high receptor density simulations with the BB beads of the receptors kept fixed.
For the thickness, the average an...
The residues on helices involved in dimer interfaces with which CHOL is in contact for more than 50% of the final microsecond of the high receptor density simulations with the receptors free to move.
Residues in contact with CHOL for more than 75% of the simulation time are in bold.
(PDF)
Plots showing the average lipid order (left column) and bilayer thickness (nm, right column) during the final 2 μs of membrane equilibration for one high receptor density simulation run of inactive (top row) or active (bottom row) receptors with fixed BB beads.
The data is averaged over all lipids, excluding the ones that flip-flop across the membr...
The correlation between the bilayer thickness and the lipid order for the high receptor density simulations of inactive (left) or activated (right) MOR with the BB beads of the receptors fixed.
For each bin, the average order is plotted vs. the average thickness.
(PDF)
Tilting of the principal axis of the active or inactive MOR in the low receptor density simulations with either restrained BB beads or freely moving receptors.
The angle θ (radial coordinate, measuring the amount of tilting) is the angle between the protein principal axis and the normal to the membrane, while φ (polar angle, representing the direct...
Normalized distribution of lipid order during the final 2 μs of membrane equilibration for lipids near inactive MOR (blue) or active MOR (red) in the high receptor density simulations with the BB beads of the receptors kept fixed.
The thick lines are the average of the five individual runs which are shown as thin lines. The individual runs are an a...
Plots showing the average the lipid order as a function of time for one of the runs in the high receptor density simulations of inactive (top row) or active (bottom row) MORs.
The data is averaged over all lipids, excluding the ones that flip-flop across the membrane (i.e. CHOL, CER, and DAG). A value of 0 (orange color) indicates a fully ordered l...
Residence time of PC (left) or cholesterol (right) during the production runs of the membrane with high receptor density.
The error bars represent the deviation over the five runs.
(PDF)
Average of the number of isolated receptors calculated as a function of time during the production runs of the membrane with high receptor density.
Values for the simulations with inactive or active receptors are reported in blue and red, respectively.
(PDF)
Model structures of the A) inactive/inactive MORs interacting at the TM1,2,H8/TM4 interface and B) active/active MORs interacting at the TM1,2,H8/TM1,2,H8 interface during the final μs of the high density simulations in which the BB beads of the receptors were kept fixed. Helices involved in the interface are colored by frequency of interaction wit...
The fraction of the final 2 μs of the low receptor density simulation with fixed receptor backbone (BB) beads during which the BB beads of the residues are in contact with the GL1 bead of a PIP1-3 lipid.
All residues listed are in contact with either the inactive or active receptor at least 10% of the simulation time. Residues exhibiting the greate...
Fraction of interfaces formed between inactive, active, and inactive/active MOR determined by clustering the conformations observed during the final microsecond of the high receptor density trajectories in which the receptors were free to move.
The mean fraction of dimers belonging to each specific interface is reported along with its 97.5% credibl...
Probability distribution of CHOL order in the headgroup region of the membrane (dashed line) and the hydrophobic part of the membrane (solid lines) during the low receptor density simulations in which the BB beads of the receptors were kept fixed.
(PDF)
The z-coordinate of the AM1 or GL1 beads as a function of lipid order for the DAG (top row) or CER (bottom row) lipids in the plasma membrane with inactive MOR, active MOR, or no receptors.
The data in the plots for the membranes with receptors are from the final 2 μs membrane equilibration in the simulations with high receptor density and the BB b...
Kinetic network of the cholesterol movement in the z-direction as a function of the distance from the protein for the A) inactive and B) active MORs generated with the plot_network routine of pyemma using the final 2 μs of membrane equilibration of the simulations with high receptor density and the BB beads of the receptors fixed. The initial geome...
Snapshot of the production runs of the simulations with high receptor density at 0, 5, 10, and 20 μs for the A) inactive, B) active, and C) mixed arrays of MOR. The lipids are in grey, the inactive proteins in blue, and the active proteins are red.
(PDF)
Movie showing the average of the lipid order as a function of time for one run with inactive receptors in the membrane with high receptor density.
The snapshots in S11 Fig were taken from this trajectory. The data is averaged over all lipids, excluding the ones that flip-flop across the membrane (i.e. CHOL, CER, and DAG). A value of 0 (orange color...
The bilayer thickness (nm, top row) and lipid order (bottom row) of the non-flipping lipids within 3.125 nm of the protein center of mass calculated as a function of the helix index during the last 2 μs of membrane equilibration of the low receptor density simulations with the BB beads of the receptors kept fixed.
For the thickness, the average and...
Average lipid thickness (upper triangle) and order (lower triangle) calculated as a function of the protein-protein distance r and the lipid position d for the following interfaces: TM5/TM5 and TM1,2,H8/TM1,2,H8 for the active MOR (panels A and B, respectively), and TM1,2,H8/TM5 for the inactive or active MOR (panels C and D, respectively). Traject...
The z-coordinate of the CHOL’s ROH or CER/DAG’s AM1 or GL1 beads as a function of the minimum distance to the BB beads of the protein for inactive MORs (top row) or active MORs (bottom row) during the final 2 μs membrane equilibration in the simulations with high receptor density and the BB beads of the receptors kept fixed.
(PDF)
The efficiency and the propensity of a drug to be bound to its target protein have been inseparable concepts for decades now. The correlation between the pharmacological activity and the binding affinity has been the first rule to design and optimize a new drug rationally. However, this argument does not prove to be infallible when the results of i...
Developing a novel drug is a complex, risky, expensive and time-consuming venture. It is estimated that the conventional drug discovery process ending with a new medicine ready for the market can take up to 15 years and more than a billion USD. Fortunately, this scenario has recently changed with the arrival of new approaches. Many novel technologi...
Developing a novel drug is a complex, risky, expensive and time-consuming venture. It is estimated that the conventional drug discovery process ending with a new medicine ready for the market can take up to 15 years and more than a billion USD. Fortunately, this scenario has recently changed with the arrival of new approaches. Many novel technologi...
The efficiency and the propensity of a drug to be bound to its target protein have been inseparable concepts for decades now. The correlation between the pharmacological activity and the binding affinity has been the first rule to design and optimize a new drug rationally. However, this argument does not prove to be infallible when the results of i...
The decay dynamics of ambient and low temperature liquid water has been investigated through all-atom molecular dynamics simulations, residence times calculations and time correlation functions from 300 K down to 243 K. Those simulations replicate the experimental value of the self-diffusion constant as a function of temperature by tuning the dampi...
The ligand migration network for O2-diffusion in truncated Hemoglobin N is analyzed based on three different clustering schemes. For coordinate-based clustering, the conventional k-means and the kinetics-based Markov Clustering (MCL) methods are employed, whereas the locally scaled diffusion map (LSDMap) method is a collective-variable-based approa...
The concentration of macromolecules inside the cell is high with respect to conventional in vitro experiments or simulations. In an effort to characterize the effects of crowding on the thermodynamics and kinetics of disordered peptides, molecular dynamics simulations were run at different concentrations by varying the number of identical weakly in...
Coherent transport promises to be the basis for an emerging new technology.
Notwithstanding, a mechanistic understanding of the fundamental principles
behind optimal scattering media is still missing. Here, complex network
analysis is applied for the characterization of geometries that result in
optimal coherent transport. The approach is tailored...
In the last decades several hydrogen-bond definitions were proposed by classical computer simulations. Aiming at validating their self-consistency on a wide range of conditions, here we present a comparative study of six among the most common hydrogen-bond definitions for temperatures ranging from 220 K to 400 K and six classical water models. Our...
Quantum transport is strongly influenced by interference with phase relations that depend on the scattering medium. As even small changes in the geometry of the medium can turn constructive interference to destructive, a clear relation between structure and fast, efficient transport is difficult to identify. Here we present a complex network analys...
At the fundamental level, our understanding of water hydrogen-bond dynamics
has been largely built on the detailed analysis of classical molecular
simulations. The latter served to develop a plethora of hydrogen bond
definitions based on different properties, including geometrical distances,
topology and energetics. Notwithstanding, no real consens...
Recent advances in computational power and simulation programs finally delivered the first examples of reversible folding for small proteins with an all-atom description. But having at hand the atomistic details of the process did not lead to a straightforward interpretation of the mechanism. For the case of the Fip35 WW-domain where multiple long...
Molecular simulations as well as single molecule experiments have been widely analyzed in terms of order parameters, the latter representing candidate probes for the relevant degrees of freedom. Notwithstanding this approach is very intuitive, mounting evidence showed that such descriptions are inaccurate, leading to ambiguous definitions of states...
Free-energy landscape theory is often used to describe complex molecular systems. Here, a microscopic description of water structure and dynamics based on configuration-space-networks and molecular dynamics simulations of the TIP4P/2005 model is applied to investigate the free-energy landscape of water. The latter is built on top of a large set of...
A mesoscopic model which allows us to identify and quantify the strength of
binding sites in DNA sequences is proposed. The model is based on the
Peyrard-Bishop-Dauxois model for the DNA chain coupled to a Brownian particle
which explores the sequence interacting more importantly with open base pairs
of the DNA chain. We apply the model to promoter...
Ion channels form pores across the lipid bilayer, selectively allowing
inorganic ions to cross the membrane down their electrochemical gradient. While
the study of ion desolvation free-energies have attracted much attention, the
role of water inside the pore is less clear. Here, molecular dynamics
simulations of a reduced model of the KcsA selectiv...
A large number of water models exists for molecular simulations. They differ in the ability to reproduce specific features of real water instead of others, like the correct temperature for the density maximum or the diffusion coefficient. Past analysis mostly concentrated on ensemble quantities, while few data was reported on the different microsco...
A large number of water models exist for molecular simulations. They differ in the ability to reproduce specific features of real water instead of others, like the correct temperature for the density maximum or the diffusion coefficient. Past analysis mostly concentrated on ensemble quantities, while few data were reported on the different microsco...
Author Summary
A complete description of complex polymers, such as proteins, includes information about their structure and their dynamics. In particular it is of utmost importance to answer the following questions: What are the structural conformations possible? Is there any relevant hierarchy among these conformers? What are the transition paths...
Comparing with community algorithms.
(0.18 MB ZIP)
Checking Markovity.
(0.56 MB ZIP)
More on Alanine dipeptide.
(<0.01 MB ZIP)
The knowledge of the Free Energy Landscape topology is the essential key to understand many biochemical processes. The determination of the conformers of a protein and their basins of attraction takes a central role for studying molecular isomerization reactions. In this work, we present a novel framework to unveil the features of a Free Energy Lan...
A new “on the fly” method to perform Born-Oppenheimer ab initio molecular dynamics (AIMD) simulations is presented. Inspired by Ehrenfest dynamics in time-dependent density functional theory, the electronic orbitals are evolved by a Schrödinger-like equation, where the orbital time derivative is multiplied by a parameter. This parameter controls th...
Flavodoxins, noncovalent complexes between apoflavodoxins and flavin mononucleotide (FMN), are useful models to investigate the mechanism of protein/flavin recognition. In this respect, the only available crystal structure of an apoflavodoxin (that from Anabaena) showed a closed isoalloxazine pocket and the presence of a bound phosphate ion, which...
A new "on the fly" method to perform Born-Oppenheimer ab initio molecular dynamics (AIMD) is presented. Inspired by Ehrenfest dynamics in time-dependent density functional theory, the electronic orbitals are evolved by a Schroedinger-like equation, where the orbital time derivative is multiplied by a parameter. This parameter controls the time scal...
We apply simple elastic network models to study some properties of the unfolding of apoflavodoxin, a protein that shows a three-state thermodynamic behavior under thermal denaturation, as revealed by extensive analysis of wildtype and mutant variants. The intermediate of apoflavodoxin presents an overall structured core, with just a part of the pro...
Knowledge of the Free Energy Landscape topology is the essential key to understanding many biochemical processes. The determination of the conformers of a protein and their basins of attraction takes a central role for studying molecular isomerization reactions. In this work, we present a novel framework to unveil the features of a Free Energy Land...
