SEARCH · PubMed Health

Results for “Molecular Dynamic simulation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed2026

Structure-based virtual screening, multi-score docking, and molecular dynamics simulation of novel small molecules targeting the epidermal growth factor receptor for potential management of oral squamous cell carcinoma.

UNLABELLED: Oral squamous cell carcinoma (OSCC) is a major global health burden, with epidermal growth factor receptor (EGFR) serving as an important therapeutic target. However, resistance to currently available EGFR inhibitors limits the efficacy of long-term treatment. In this study, a structure-based virtual screening approach was employed using the Mcule database to identify novel small molecules with potential EGFR-inhibitory activity. The top-ranked compounds were subjected to consensus docking using multiple docking platforms and compared with established EGFR inhibitors. The most promising complexes were further evaluated using 500 ns molecular dynamics simulations to investigate their structural stability, conformational flexibility, and binding persistence. ADMET and pharmacokinetic analyses were performed to assess the drug-like and safety profiles. Five lead compounds (C1-C5) demonstrated significant binding affinities toward EGFR, ranging from - 9.9 to - 9.2 kcal/mol, while satisfying the major drug-likeness criteria. Molecular dynamics simulations suggested that C1 and C4 may form relatively stable EGFR-ligand complexes, as supported by stable RMSD convergence and persistent interactions with key active-site residues throughout the simulation period. Trajectory-based interaction analyses further indicated a sustained binding behavior. ADMET profiling predicted favorable oral bioavailability and low predicted toxicity for most compounds, particularly C3 and C5, although a potential risk of cytochrome P450-mediated drug-drug interactions was observed. Overall, the shortlisted compounds exhibited docking and dynamic stability profiles comparable to those of the reference inhibitor Lapatinib. These findings suggest the potential therapeutic relevance of structurally novel EGFR-targeting scaffolds in OSCC and provide a foundation for future experimental validation through in vitro and in vivo studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00722-4.

ADMET↗

PubMed1991

Molecular dynamics simulations of small peptides: dependence on dielectric model and pH.

There has been much interest recently in the structure of small peptides in solution. A recent study by Bradley and co-workers [(1989) in Techniques of Protein Chemistry, Hugli, T.E., Ed., Academic Press, Orlando, FL, pp. 531-546; (1990) Journal of Molecular Biology, 215, pp. 607-622] describes a 17-residue peptide that is stable as a monomeric helix in aqueous solution at low pH, as determined by two-dimensional nmr and CD spectroscopy. They also have determined the helix content of the peptide as a function of pH using CD. We performed molecular dynamics simulations, with an empirical force field, of this peptide at low pH, with three different dielectric models: a linear distance-dependent dielectric function (epsilon = R); a modified form [J. Ramstein and R. Lavery (1988) Proceedings of the National Academy of Science, USA, Vol. 85, pp. 7231-7235] of the sigmoidal distance-dependent dielectric function of Hingerty and co-workers [(1985) Biopolymers, Vol. 24, pp. 427-439]; and epsilon = 1 with the peptide immersed in a bath of water molecules. We found that simulations with the sigmoidal dielectric function and the model with explicit water molecules resulted in average distances for particular interactions that were consistent with the experimental nmr results, with the sigmoidal function best representing the data. However, these models exhibited very different helix-stabilizing interactions. We also performed simulations using the sigmoidal function at moderate and high pH to compare to experimental determinations of the pH dependence of helix content. Helix content did not decrease with increases in pH, as shown experimentally. We did, however, observe changes in a specific side chain-helix dipole interaction that was implicated in determining the pH-dependent behavior of this peptide. Overall, the sigmoidal dielectric function was a reasonable alternative to adding explicit water molecules. In comparing 100 ps molecular dynamics simulations, the sigmoidal function was much less computer intensive and sampled more of conformational space than the treatment using explicit water molecules. Sampling is especially important for this system since the peptide has been shown experimentally to populate both helical and nonhelical conformations.

Amino Acid Sequence↗

PubMed1986

Molecular dynamics simulation study of a two-dimensional fluid mixture system: a model for biological membranes.

The computer simulation technique of molecular dynamics was applied to a model two-dimensional fluid mixture system to examine the short-range ordering of lipid and protein molecules in biological membranes. The model system consists of small disks (lipids) and large disks (proteins) with a radius ratio of 6, constrained to move in a plane. The particles interact with pairwise additive repulsive short range potentials, so as to simulate hard disks. Periodic boundary conditions are assumed in order to minimize boundary effects. For values of the number density of the small disks and of the temperature appropriate for a lipid membrane, the fraction, f, of small disks 'next to' at least one large disk was computed by molecular dynamics. This was done as a function of concentration and for several definitions of 'next to'. The molecular dynamics results show that, at moderately low mole fractions of the large disks, the calculated values of f deviate noticeably from the linear relation which would be expected in the absence of protein-protein proximity effects. The results are discussed in terms of current models of lipid-protein ordering in biological membranes.

Computers↗

PubMed1992

Combined use of molecular dynamics simulations and NMR to explore peptide bond isomerization and multiple intramolecular hydrogen-bonding possibilities in a cyclic pentapeptide, cyclo(Gly-Pro-D-Phe-Gly-Val).

The conformational behavior of a model cyclic pentapeptide--cyclo(Gly-L-Pro-D-Phe-Gly-L-Val)--has been explored through the combined use of in vacuo molecular dynamics simulations and a range of nmr experiments (preceding paper). The molecular dynamics analysis suggests that, despite the conformational constraints imposed by formation of the pentapeptide cycle, this pentapeptide undergoes conformational transitions between various hydrogen-bonded conformations, characterized by low energy barriers. An inverse gamma turn with Pro in position i + 1 and a gamma turn with D-Phe in position i + 1 are two alternatives occurring frequently. Like other DLDDL cyclic pentapeptides, cyclo(Gly-Pro-D-Phe-Gly-Val) is also stabilized by an inverse gamma-turn structure with the beta-branched Val residue in position i + 1, and this hydrogen bond is retained in the different conformational families. The gamma-turn around D-Phe3 and the inverse gamma turn around Val5 are consistent with the nmr observations. 3JNH-CH alpha coupling constants of the all-trans forms were calculated from one of the molecular dynamics trajectories and are comparable to nmr experimental data, suggesting that the conformational states visited during the simulation are representative of the conformational distribution in solution. In addition to the equilibrium among various hydrogen-bonded all-trans conformers, the observation in nmr spectra of two sets of resonances for all peptide protons indicated a slow conformational interconversion of the Gly-Pro peptide bond between trans and cis isomers. The activation energy between these two conformers was determined experimentally by magnetization transfer and was calculated by high temperature constrained molecular dynamics simulation. Both methods yield a free energy of activation of ca. 20 kcal/mol. Furthermore, the free energy of activation is dependent on the direction of rotation of the Gly-Pro peptide bond.

Amino Acid Sequence↗

PubMed1986

Molecular dynamics simulations of native and substrate-bound lysozyme. A study of the average structures and atomic fluctuations.

Molecular dynamics simulations of hen egg-white lysozyme in the free and substrate-bound states are reported and the nature of the average structures and atomic fluctuations are analyzed. Crystallographic water molecules of structural importance, as determined by hydrogen-bonding, were included in the simulations. Comparisons are made between the dynamics and the X-ray results for the atomic positions, the main-chain and side-chain dihedral angles, and the hydrogen-bonding geometry. Improvements over earlier simulations in the potential energy function and methodology resulted in stable trajectories with the C alpha co-ordinates within 1.5 A of the starting X-ray structure. Structural features analyzed in the simulations agreed well with the X-ray results except for some surface residues. The Asx chi 2 dihedral distribution and the geometry of hydrogen bonding at reverse turns show differences; possible causes are discussed. The relation between the magnitudes and time-scales of the residue fluctuations and secondary structural features, such as helices beta-sheets and coiled loops, is examined. Significant differences in the residue mobilities between the simulations of the free and substrate-bound states were found in a region of the enzyme that is in direct contact with the substrate and in a region that is distant from the active-site cleft. The dynamic behavior of the structural water molecules is analyzed by examining the correlation between the fluctuations of the water oxygens and the lysozyme heavy-atoms to which they are hydrogen-bonded.

Animals↗

PubMed1991

Molecular dynamics simulations of the unfolding of an alpha-helical analogue of ribonuclease A S-peptide in water.

Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS have been conducted in aqueous solution for 300 ps at 278 K and for 500 ps in two different runs at 358 K. The results show agreement with experimental observations in that at low temperature, 5 degrees C, the helix is stable, while unfolding is observed at 85 degrees C. In the low-temperature simulation a solvent-separated ion pair was formed between Glu-2 and Arg-10, and the side chain of His-12 reoriented toward the C-terminal end of the alpha-helix. Detailed analyses of the unfolding pathways at high temperature have also revealed that the formation or disappearance of main-chain helical hydrogen bonds occurs frequently through an alpha in equilibrium with 3(10) in equilibrium with no hydrogen bond sequence.

Amino Acid Sequence↗

PubMed1992

Differential helix propensity of small apolar side chains studied by molecular dynamics simulations.

A series of oligoalanine molecules with single amino acid replacements in the middle of the chain has been studied by molecular dynamics simulations. Differences in stability of the alpha-helix (as free energies delta delta G degrees) were estimated for the following series of residues: alpha-aminoisobutyric acid, alanine, alpha-amino-n-butyric acid, valine, glycine, D-alanine, t-leucine (= alpha-amino-beta,beta-dimethyl-n- butyric acid), and proline, arranged here in decreasing order of helix-forming potential. (The results for proline and valine had been reported earlier.) No experimental results were available for alpha-amino-n-butyric acid, D-alanine, and t-leucine at the time these calculations were done. The values of delta delta G degrees, including the three predictions, are in striking agreement with recent experimental results. A combination of free dynamics, dynamics with forced conformational change, and dynamics with forced molecular replacement was used. Conformational distributions were calculated for the peptide backbone of the dipeptides and, where appropriate, for the side chains of the dipeptide and the alpha-helix. The results demonstrate an unexpected level of accuracy for the all-atom model used to represent atomic interactions in the simulations. The simulations permit a detailed analysis of different factors responsible for conformational preferences and differences in stability. These conclusions drawn from this analysis agree with accepted qualitative explanations and allow these explanations to be quantitated to an extent not heretofore possible.

Alanine↗

PubMed1985

A molecular dynamics simulation of double-helical B-DNA including counterions and water.

We present the results of an atomic level molecular dynamical simulation of a 5-base-pair fragment of double-helical DNA with inclusion of water and sodium counterions and a complete description of their electrostatic interactions. The shape of the double helix is preserved throughout the simulation, and the helix repeat is calculated to be 10.0, in reasonable agreement with experimental results. The most flexible conformational angles in the structure are the glycosidic angle and the sugar pucker.

Computers↗

PubMed1990

Solution structure studies of d(AC)4.d(GT)4 via restrained molecular dynamics simulations with NMR constraints derived from two-dimensional NOE and double-quantum-filtered COSY experiments.

The structure of d(AC)4.d(GT)4 is investigated by constrained molecular dynamics simulations. The constraints include proton pair distances derived from 2D NOE intensities by using the iterative relaxation matrix analysis algorithm MARDIGRAS and sugar pucker phases and amplitudes derived from double-quantum-filtered COSY spectra. Molecular dynamics runs on simulated intensity and distance sets as well as the experimental data were carried out to determine the effects of starting structure, distance constraint derivation, energy functions, and experimental errors on the end result. It was found that structural details could not be elucidated within about 1.5-A overall atomic deviation. This limitation is due in part to the accuracy of the experimental data but, more importantly, is attributable to the quantity of experimental constraints available and to imperfections in the force field utilized in the molecular dynamics calculations. Within the limits of the method, some structural characteristics of d(AC)4.d(GT)4 could be elucidated.

Computer Simulation↗

PubMed1989

An NMR-based molecular dynamics simulation of the interaction of the lac repressor headpiece and its operator in aqueous solution.

The results of a 125 psec molecular dynamics simulation of a lac headpiece-operator complex in aqueous solution are reported. The complex satisfies essentially all experimental distance information derived from two-dimensional nuclear magnetic resonance (2-D-NMR) studies. The interaction between lac repressor headpiece and its operator is based on many direct- and water-mediated hydrogen bonds and nonpolar contacts which allow the formation of a tight complex. No stable hydrogen bonds between side chains and bases are found, while specific contacts occur between both nonpolar groups and, to a lesser extent, through water-mediated hydrogen bonds. The simulated complex structure in water is intrinsically stable without application of nuclear Overhauser effect (NOE) distance restraints, while being compatible with most of the available biochemical, genetic, and chemically induced dynamic nuclear polarization (CIDNP) data.

Binding Sites↗

PubMed1991

Motion of aromatic side chains, picosecond fluorescence, and internal energy transfer in Escherichia coli thioredoxin studied by site-directed mutagenesis, time-resolved fluorescence spectroscopy, and molecular dynamics simulations.

We have determined the picosecond fluorescence of the four aromatic amino acid residues (W28, W31, Y49, and Y70) in wild-type Escherichia coli thioredoxin (wt Trx) and a mutant Trx with W31 replaced by phenylalanine, Trx-W28-W31F. The internal motions of the four aromatic side chains were also analyzed. We examined the possibility of using internal energy transfer from tyrosine to tryptophan as a measure of long-range distances. The major features of the lifetime distribution of tryptophan fluorescence were unchanged in the W31F mutation, indicating that the environment of W28 is similar in both wt Trx and Trx-W28-W31F. However, the mutation of W31F changed the mobility of W28, situated close to the active-site disulfide/dithiol, but not the mobility of two tyrosines, Y49 and Y70, situated on the other side of the molecule. The mobility of the two tyrosine residues increased upon reduction of the active-site disulfide, indicating a looser structure with reduction. This increased motion could also be seen from molecular dynamics simulations. The change in energy transfer rates, as judged by tyrosine fluorescence lifetimes, was in agreement with energy transfer rates calculated from the molecular dynamics simulations. The anisotropy of tryptophan and tyrosine fluorescence could be separated in three parts: (I) overall rotation of the protein (10(-9)s), (II) internal mobility of side chains (10(-10)s), and (III) a very fast relaxation (10(-12)s). We can only experimentally detect this very fast relaxation when the internal motion is not present.

Amino Acids↗

PubMed1992

A molecular dynamics simulation of a polyamine-induced conformational change of DNA. A possible mechanism for the B to Z transition.

A 75ps molecular dynamics simulation has been performed on a fully solvated complex of spermine with the B DNA decamer (dGdC)5.(dGdC)5. The simulation indicates a possible mechanism by which polyamines might induce the formation of a left-handed helix, the B to Z transition. Spermine was initially located in the major groove, hydrogen bonded to the helix. During the simulation the ligand migrates deeper into the DNA, maintaining strong hydrogen bonding to the central guanine bases and destroying the Watson-Crick base pairing with their respective cytosines. Significant rotation of these and other cytosine bases was observed, in part due to interactions of the helix with the aminopropyl chains of spermine. An intermediate BII conformation might be of importance in this process.

Base Sequence↗

PubMed1988

Molecular dynamics simulations of ribonuclease T1: analysis of the effect of solvent on the structure, fluctuations, and active site of the free enzyme.

Molecular dynamics simulations were performed on ribonuclease T1 (RNase T1; EC 3.1.27.3) to determine a structure for the free enzyme. Simulations starting with the X-ray coordinates for the 2'GMP-RNase T1 complex were done in vacuo and with an 18-A water ball around the active site using stochastic boundary conditions to understand the influence of water on both the structure and fluctuations of the enzyme. Removal of 2'GMP caused structural changes in the loop regions, including those directly interacting with the bound inhibitor in the crystal structure, while regions of secondary structure were less affected. The presence of solvent in the simulation damped the structural changes observed, which may be related to the use of full charges in both simulations. Fluctuations were also affected by the water, which generally increased both at the surface and in the interior of the protein. The active site in vacuo collapsed upon itself, forming a number of protein-protein hydrogen bonds leading to larger structural changes and lowered fluctuations while the presence of water kept the active site open, minimized structural changes, and increased fluctuations. Such fluctuations in the active site may be important for the binding of inhibitors or substrates to the enzyme. Lastly, results from the water simulation allow the prediction of a motion for a hypothetical tryptophan at position 45, which can ultimately be tested experimentally via time-resolved fluorescence using a site-specific mutant of the enzyme.

Aspergillus oryzae↗

PubMed1992

A 500 ps molecular dynamics simulation study of interleukin-1 beta in water. Correlation with nuclear magnetic resonance spectroscopy and crystallography.

We report the results of a 500 ps molecular dynamics simulation of the cytokine interleukin-1 beta, a protein of 153 amino acids, immersed in a sphere of 3783 bulk water molecules with a radius of 33 A. The simulation reproduces the amplitudes of the fast librational motions of the backbone N-H bonds determined from 15N nuclear magnetic relaxation data, as well as the crystallographic B-factors. Moreover, this study suggests a molecular picture of the nature of the slow internal motions that have been inferred from nuclear magnetic resonance relaxation experiments. These experiments indicated that, in addition to fast motions common to all residues, 32 surface residues exhibit slow motions on the 400 ps to 5 ns time-scale. While the present simulation is not sufficiently long to provide a quantitative description of events on this time-scale, it is long enough to observe several large amplitude transitions that are likely candidates for these slow motions. Specifically, in many of these 32 residues, the N-H groups are hydrogen bonded and infrequent dihedral transitions cause the N-H vectors to jump between states with well-defined orientations. It is shown that the time course of the angular reorientational correlation functions of these residues calculated from the trajectory is a reflection of the random times at which these infrequent jumps happen to have occurred. Thus, while the rate of these transitions cannot be quantified, the simulated decay of these correlation functions is completely consistent with the physical picture in which the N-H vectors, in addition to fast librational motion, undergo large amplitude jumps between conformations stabilized by hydrogen bonds.

Computer Simulation↗

PubMed2025

Exploring potential targets and molecular mechanisms of traumatic brain injury exacerbated by Benzo(a)pyrene via network toxicology and molecular dynamics simulation.

Benzo(a)pyrene (BaP) is a common environmental pollutant from combustion sources that promotes oxidative stress, neuroinflammation and disruption of blood-brain barrier (BBB). However, its contribution to worsening traumatic brain injury (TBI) remains unclear. In this study, we aimed to assess the contribution of BaP to secondary injury in TBI. By integrating data from e.g., the Comparative Toxicogenomics Database, GeneCards, and Online Mendelian Inheritance in Man, 121 overlapping core targets were identified between BaP and TBI. Enrichment analyses via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, combined with protein-protein interaction networks and topological algorithms (degree, closeness centrality, betweenness centrality, average shortest path length, topological coefficient and partner of multi-edged node pairs), highlighted five hub genes (TP53, EGFR, AKT1, ACTB, and TNF) implicated in mitogen-activated protein kinase signaling, oxidative stress, and neuroinflammation. Molecular docking showed strong binding affinities of BaP to these hub proteins, with energies from -9.3 to -12.1 kcal/mol, tighter than co-crystal ligands and existing protein-binding drugs. Molecular dynamics simulations confirmed interaction stability through low root-mean-square deviation (< 0.5 nm), fluctuation, and radius of gyration values. Calculation of binding free energies using MM-PBSA validated the strong binding affinity between BaP and binding pockets of each hub genes. Toxicity prediction analysis revealed an oral LD50 of 316 mg/kg for BaP, with high probabilities for neurotoxicity, BBB permeability, carcinogenicity, and mutagenicity, associated with aryl hydrocarbon receptor activation. These findings reveal a "neurovascular homeostasis disruption" network underlying BaP-exacerbated TBI pathology and highlight potential targets to reduce pollution-related risks in TBI management.

Benzo(a)pyrene↗

PubMed1987

Molecular dynamics simulations of fluorescence polarization of tryptophans in myoglobin.

The fluorescence of heme proteins is influenced by energy transfer from the excited tryptophan to the heme. Molecular dynamics simulations of the tryptophan and heme motions in sperm whale myoglobin were used to calculate the fluorescence intensity and anisotropy decays. The side chains underwent both small rapid orientational fluctuations and large infrequent transitions between conformations. The predicted motions of the tryptophans and the heme produce large fluctuations in the instantaneous rate of energy transfer, but no stable conformations in which energy transfer is suppressed were found. The calculated fluorescence anisotropies exhibited a large subpicosecond decay, corresponding to nondiffusive side-chain motions. The calculations adequately predict the observed fluorescence decay curve for myoglobin and the total anisotropy decay at 16-ps time resolution. The subnanosecond decays of anisotropy for tryptophan-14 in tuna myoglobin are not reproduced by the calculation.

Animals↗

PubMed1988

Molecular-dynamics simulations of [Met5]- and [D-Ala2,Met5]-enkephalins. Biological implication of monomeric folded and dimeric unfolded conformations.

To investigate the biologically active conformation of enkephalin, molecular-dynamics simulations were applied to [Met5]- and [D-Ala2,Met5]-enkephalins. The dynamic trajectory of monomeric extended [Met5]-enkephalin was analysed in terms of relative mobility between respective torsions of backbone chain. After 10 ps of the dynamics simulation, the conformational transition was converged into a stationary state among the beta-bend folded forms, where they are stabilized by several intramolecular hydrogen-bond formations. Similar conformational transition was also observed in the dynamics simulation of [D-Ala2,Met5]enkephalin, which is a more mu-receptor-specific peptide than [Met5]enkephalin. The geometrical correspondence between the monomeric enkephalin conformation in the stationary state and morphine molecule (a mu-specific rigid opiate) was surveyed by virtue of the triangular substructures generated by choosing three functional atoms in each molecule, and good resemblances were observed. On the other hand, the dynamics simulation of the antiparallel extended [Met5]enkephalin dimer showed a trajectory different from that of the monomeric one. Two intermolecular hydrogen bonds at Tyr1 (NH3+)...Met5(CO2-) end residues were held throughout the 100 ps simulation, the dimeric structure being consequently kept. The conformational transition of the backbone chains from the antiparallel extended form to the twisted one took place via an intermediate state. Many conformations revealed during the dynamics simulation showed that the relative orientations of each two Tyr1, Gly3, Phe4 and Met5 residues in the dimer are nearly related by a pseudo-C2-symmetry respectively, and both halves of the dimer structure could be further fitted to the monomeric folded enkephalin conformation. The monomeric and dimeric conformations of enkephalin at their stationary states are discussed in relation to the substrate-specificity for mu- and delta-opioid receptors.

Computer Simulation↗

PubMed2026

Molecular dynamics simulations of positively selected codons in FcγRI reveal novel biochemical binding properties.

FcγRI is a high-affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody-based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood, and to address this we explored signatures of positive selection in the receptor's functional gene, FCGR1A, using codon-based selection tests on aligned 1-1 orthologous sequences from placental mammals (n = 32). Signatures of positive selection have occurred at several locations within the gene, with two sites (H148 (M2a ω 0.997 & M8 ω = 0.993)) and (W149 (M2a ω = 0.999 & M8 ω = 1.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the FcγRI-IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H148P and W149R codons at different nodes in the phylogeny. Employing molecular dynamics simulations, we determined how evolutionary changes at these sites may have influenced the binding of FcγRI-IgG of modern-day Homo sapiens. Measuring RMSD, free energy, radius of gyration, hydrogen bond formation, and analyzing free energy landscapes, we demonstrate that structural instability between mutant structures vs the WT counterpart; however, overall binding potential increases at position 148, yet decreases at 149 in potential. H148P protonation at physiological pH remains similar, yet during acidotic calculations, protonation is likely reduced, with predicted reduction in affinity for IgG. While ancestral W149R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding FcγRI-IgG interface, our data demonstrate that these two codons have evolved in humans to be relatively insensitive to shifts in pH promoting a more stable interaction with the Fc portion of IgG during diseases that promote acidosis.

Receptors, IgG↗