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PubMed1996

Glass transition in DNA from molecular dynamics simulations.

Molecular dynamics simulations of the oligonucleotide duplex d(CGCGCG)2 in aqueous solution are used to investigate the glass transition phenomenon. The simulations were performed at temperatures in the 20 K to 340 K range. The mean square atomic fluctuations showed that the behavior of the oligonucleotide duplex was harmonic at low temperatures. A glass transition temperature at 223 K to 234 K was inferred for the oligonucleotide duplex, which is in agreement with experimental observations. The largest number of hydrogen bounds between the polar atoms of the oligonucleotide duplex and the water molecules was obtained at the glass transition temperature. With increasing temperature we observed a decrease in the average lifetime of the hydrogen bonds to water molecules.

Base Sequence↗
PubMed1996

Dimer asymmetry in superoxide dismutase studied by molecular dynamics simulation.

Molecular dynamics (MD) simulations of 100 ps have been carried out to study the active-site behaviour of the Cu,Zn superoxide dismutase dimer (SOD) in water. The active site of each subunit was monitored during the whole simulation by calculating the distances between functional residues and the catalytic copper. The results indicate that charge orientation is maintained at each active site but the solvent accessibility varies. Analysis of the MD simulation, carried out by using the atomic displacement covariance matrix, has shown a different intra-subunit correlation pattern for the two monomers and the presence of inter-subunit correlations. The MD simulation presented here indicates an asymmetry in the two active sites and different dynamic behaviour of the two SOD subunits.

Animals↗
PubMed1993

Protein hydration elucidated by molecular dynamics simulation.

Molecular dynamics (MD) simulation covering a wide range of hydration indicate that myoglobin is fully hydrated by 350 water molecules, in agreement with experiment. These waters, originally placed uniformly about the protein, form clusters that hydrate every charged group throughout the entire simulation. Some atoms in charged groups are hydrated by two water layers while 37% of the protein surface remains uncovered. The locations of the 350 waters are consistent with those of crystallographic waters resolved by x-ray and neutron diffraction. Hydration by 350 waters at 300 K stabilizes the conformation of carboxymyoglobin measured by x-ray diffraction throughout the entire protein, halves the rate of torsional transitions, and promotes alternative conformations for surface atoms. The glass transition observed experimentally in hydrated myoglobin near 220 K is also seen in the simulations and correlates with an increase in the number of dihedral angles undergoing transitions. The anharmonic protein motion above 220 K is enhanced by protein hydration.

Computer Simulation↗
PubMed1993

A model for the dynemicin-A cleavage of DNA using molecular dynamics simulation.

Molecular dynamics (MD) simulations to model possible reaction pathways of the dynemicin-A-DNA cleavage mechanism were performed. Two base-pairs sequences, ApCpTpApCpTp-3'/TpGpApTpGpAp-5' and CpApCpGpGpGp-3'/GpTpGpCpCpCp-5', were considered in the calculations. A model based on a prior study of intercalation of dynemicin-A and posterior activation of the drug was assumed in this study. The minimum energy minor groove intercalation complexes for dynemicin-A were used as starting structures in the MD simulations for the reactive intermediate species involved in the postulated action mechanism. The dynemicin-A diol derivative product of the opening of the epoxy ring was used as a "steric mimic" ligand for the DNA-reactive diaryl intermediate. The calculated changes in the geometry of the intercalation complex, due to the opening of the epoxy ring, correspond to the approach of the postulated intermolecular reaction centers in the intercalation states that are responsible for the highest observed DNA cleavage frequency observed. Conversely, unfavorable reaction geometries were found for the intercalation modes corresponding to the lowest observed DNA cutting frequencies.

Anthraquinones↗
PubMed2003

Effects of a carane derivative local anesthetic on a phospholipid bilayer studied by molecular dynamics simulation.

Molecular dynamics (MD) simulations of two hydrated palmitoyloleoylphosphatidylcholine (POPC) bilayers each containing eight carane derivative (KP-23) local anesthetic (LA) molecules in neutral (POPC-LA) or protonated (POPC-LAH) forms were carried out to investigate the effect of KP-23 and its protonation on the bilayer. 3-ns trajectories were used for analyses. A pure POPC bilayer was employed as a reference system. In both POPC-LA and POPC-LAH systems a few KP-23 molecules intercalated into the bilayer and moved near the bilayer/water interface. They were located on the hydrophobic core side of the interface in the POPC-LA bilayer, but on the water phase side in the POPC-LAH bilayer. The order of the POPC chains was higher in the POPC-LA bilayer than in the pure POPC bilayer and was lower in the POPC-LAH bilayer. Interactions between polar groups of KP-23 and POPC or water were responsible for a lower hydration of POPC headgroups in POPC bilayers containing KP-23 than in the pure POPC bilayer. KP-23 molecules were found to form aggregates both in POPC-LA and POPC-LAH bilayers. Due to higher amphiphilicity of LAH, the LAH aggregate was more micelle-like and larger than the LA one. The results demonstrate the rapid timescales of the initial processes that take place at and near the bilayer interface as well as details of the atomic level interactions between local anesthetic and the lipid matrix of a cell membrane.

Anesthetics, Local↗
PubMed2002

Bridge function and other structural properties of core-softened model fluids from molecular dynamics simulations.

Molecular dynamics (MD) simulations in three dimensions have been performed for a fluid with particles interacting with a continuous version of the Stell-Hemmer core-softened potential that in two dimensions has been known to reproduce most of the static and dynamic anomalies of liquid water. The pair distribution function obtained from the MD simulation is extrapolated with the help of integral equation theory with a suitable closure relation and the bridge function is extracted. A strong dependence of the bridge function on the system size, i.e., the total number of particles (N) used in the simulation box is observed, which leads to spurious values of the structure factor at long wavelengths. A simple self-consistent correction scheme for the finite size effect has been adopted to correct the bridge function and this scheme produces the correct bridge function even for a small system size. The effects of temperature, number density, and potential parameters on the pair distribution functions and extracted bridge functions are extensively studied.

Journal Article↗
PubMed1995

Dramatic differences in the motions of the mouth of open and closed cytochrome P450BM-3 by molecular dynamics simulations.

Molecular dynamics trajectories were calculated separately for each of the two molecules in the asymmetric unit of the crystal structure of the hemoprotein domain of cytochrome P450BM-3. Each simulation was 200 ps in length and included a 10 A layer of explicit solvent. The simulated time-average structure of each P450BM-3 molecule is closer to its crystal structure than the two molecular dynamics time-averaged structures are to each other. In the crystal structure, molecule 2 has a more accessible substrate binding pocket than molecule 1, and this difference is maintained throughout the simulations presented here. In particular, the substrate docking regions of molecule 1 and molecule 2 diverge in the solution state simulations. The mouth of the substrate binding pocket is significantly more mobile in the simulation of molecule 2 than in the simulation of molecule 1. For molecule 1, the width of the mouth is only slightly larger than its X-ray value of 8.7 A and undergoes fluctuations of about 1 A. However, in molecule 2, the mouth of the substrate binding pocket is dramatically more open in the time-average molecular dynamics structure (14.7 A) than in the X-ray structure (10.9 A). Furthermore, this region of the protein undergoes large amplitude motions during the trajectory that are not seen in the trajectory of molecule 1, repeatedly opening and closing up to 7 A. Presumably, the binding of different substrates will induce the mouth region to adopt different conformations from within the wide range of structures that are accessible.

Binding Sites↗
PubMed1993

Mechanism for the rotamase activity of FK506 binding protein from molecular dynamics simulations.

Molecular dynamics (MD) and free energy perturbation (FEP) methods are used to study the binding and mechanism of isomerization of a tetrapeptide (AcAAPFNMe) by FK506 binding protein (FKBP). Detailed structures are predicted for the complexes of FKBP with the peptide in both ground-state and transition-state forms. The results support a mechanism of catalysis by distortion, where a large number of nonbonded interactions act together to stabilize preferentially the twisted transition state. The two most important groups for the catalysis are suggested to be Trp59 and Asp37, but several other groups are identified as directly or indirectly involved in the binding and catalysis. However, the structural results do not support the notion that the keto oxygen of the immunosuppressive agents FK506 and rapamycin mimics the oxygen for the twisted peptide bond in the FKBP-transition-state complex.

Amino Acid Sequence↗
PubMed1994

Computer simulations of cyclic and acyclic cholinergic agonists: conformational search and molecular dynamics simulations.

Molecular dynamics simulations have been performed on aqueous solutions of two chemically similar nicotinic cholinergic agonists in order to compare their structural and dynamical differences. The cyclic 1,1-dimethyl-4-acetylpiperazinium iodide (HPIP) molecule was previously shown to be a strong agonist for nicotinic acetylcholine receptors (McGroddy et al., 1993), while the acyclic N,N,N,N'-tetramethyl-N'-acetylethylenediamine iodide (HTED) derivative is much less potent. These differences were expected to arise from differences in the solution structures and internal dynamics of the two molecules. HPIP was originally thought to be relatively rigid; however, molecular dynamics simulations suggest that the acetyl portion of the molecule undergoes significant ring dynamics on a psec timescale. The less constrained HTED molecule is relatively rigid, with only one transition observed about any of the major dihedrals in four 100 psec simulations, each started from a different conformation. The average structures obtained from the simulations are very similar to the starting minimized structure in each case, except for the HTED simulation where a single rotation about the N-C-C-N(+) backbone occurred. In each case, HTED had three to five more water molecules in its primary solvation shell than HPIP, indicating that differences in the energetics of desolvation before binding may partially explain the increased potency of HPIP as compared to HTED.

Biophysical Phenomena↗
PubMed1990

Using molecular dynamics simulations on crambin to evaluate the suitability of different continuum dielectric and hydrogen atom models for protein simulations.

Molecular dynamics simulations of enzymes with enough explicit waters of solvation to realistically account for solute-solvent interactions can burden the computational resources required to perform the simulation by more than two orders of magnitude. Since enzyme simulations even with an implicit solvation model can be imposing for a supercomputer, it is important to assess the suitability of different continuum dielectric models for protein simulations. A series of 100-picosecond molecular dynamics simulations were performed on the X-ray crystal structure of the protein crambin to examine how well computed structures, obtained using seven continuum dielectric and two hydrogen atom models, agreed with the X-ray structure. The best level of agreement between computed and experimental structures was obtained using a constant dielectric of 2 and the all-hydrogen model. Continuum dielectric models of 1, 1r, and 2r also led to computed structures in reasonably good agreement with the X-ray structure. In all cases, the all-hydrogen model gave better agreement than the united atom model, although, in one case, the difference was not significant. Dielectric models of 4, 80, and 4r with either hydrogen model yielded significantly poorer fits. It is especially noteworthy that the observed trends did not semiquantitatively converge until about 50 picoseconds into the simulations, suggesting that validation studies for protein calculations based on energy minimizations or short simulations should be viewed with caution.

Computer Simulation↗
PubMed1995

Fluctuation and cross-correlation analysis of protein motions observed in nanosecond molecular dynamics simulations.

Nanosecond molecular dynamics simulations of bovine pancreatic trypsin inhibitor and lysozyme in water are analyzed in terms of backbone atomic positional fluctuations and dynamical cross-correlations. It is found that although the molecular systems are stable, B-factors calculated over a time period as long as 500 ps are not representative for the motions within the proteins. This is especially true for the most mobile residues. On a nanosecond time-scale, the B-factors calculated from the simulations of the proteins in solution are considerably larger than those obtained by structure refinement of the proteins in crystals, based on X-ray data. The time evolution of the atomic fluctuations shows that for large portions of the proteins under study, atomic positional fluctuations are not yet converged after a nanosecond. Cross-correlations do not converge faster than the fluctuations themselves. Most display very erratic behavior if the sampling covers less than about 200 ps. It is also shown that inclusion of mobile atoms into the procedure used to remove rigid-body motion from the simulation can lead to spurious correlations between the motions of the atoms at the surface of the protein.

Animals↗
PubMed2003

Interactions of the designed antimicrobial peptide MB21 and truncated dermaseptin S3 with lipid bilayers: molecular-dynamics simulations.

Molecular-dynamics simulations covering 30 ns of both a natural and a synthetic antimicrobial peptide in the presence of a zwitterionic lipid bilayer were performed. In both simulations, copies of the peptides were placed in an alpha-helical conformation on either side of the bilayer about 10 A (1 A=0.1 nm) from the interface, with either the hydrophobic or the positively charged face of the helix directed toward the bilayer surface. The degree of peptide-lipid interaction was dependent on the starting configuration: surface binding and subsequent penetration of the bilayer was observed for the hydrophobically oriented peptides, while the charge-oriented peptides demonstrated at most partial surface binding. Aromatic residues near the N-termini of the peptides appear to play an important role in driving peptide-lipid interactions. A correlation between the extent of peptide-lipid interactions and helical stability was observed in the simulations. Insertion of the peptides into the bilayer caused a dramatic increase in the lateral area per lipid and decrease in the bilayer thickness, resulting in substantial disordering of the lipid chains. Results from the simulations are consistent with early stages of proposed mechanisms for the lytic activity of antimicrobial peptides. In addition to these 'free' simulations, 25 ns simulations were carried out with the peptides constrained at three different distances relative to the bilayer interface. The constraint forces are in agreement with the extent of peptide-bilayer insertion observed in the free simulations.

Amino Acid Sequence↗
PubMed1999

Charge pairing of headgroups in phosphatidylcholine membranes: A molecular dynamics simulation study.

Molecular dynamics simulation of the hydrated dimyristoylphosphatidylcholine (DMPC) bilayer membrane in the liquid-crystalline phase was carried out for 5 ns to study the interaction among DMPC headgroups in the membrane/water interface region. The phosphatidylcholine headgroup contains a positively charged choline group and negatively charged phosphate and carbonyl groups, although it is a neutral molecule as a whole. Our previous study (Pasenkiewicz-Gierula, M., Y. Takaoka, H. Miyagawa, K. Kitamura, and A. Kusumi. 1997. J. Phys. Chem. 101:3677-3691) showed the formation of water cross-bridges between negatively charged groups in which a water molecule is simultaneously hydrogen bonded to two DMPC molecules. Water bridges link 76% of DMPC molecules in the membrane. In the present study we show that relatively stable charge associations (charge pairs) are formed between the positively and negatively charged groups of two DMPC molecules. Charge pairs link 93% of DMPC molecules in the membrane. Water bridges and charge pairs together form an extended network of interactions among DMPC headgroups linking 98% of all membrane phospholipids. The average lifetimes of DMPC-DMPC associations via charge pairs, water bridges and both, are at least 730, 1400, and over 1500 ps, respectively. However, these associations are dynamic states and they break and re-form several times during their lifetime.

Binding Sites↗
PubMed2000

Structure of the Sm binding site from human U4 snRNA derived from a 3 ns PME molecular dynamics simulation.

A molecular dynamics simulation of the Sm binding site from human U4 snRNA was undertaken to determine the conformational flexibility of this region and to identify RNA conformations that were important for binding of the Sm proteins. The RNA was fully-solvated (>9,000 water molecules) and charge neutralized by inclusion of potassium ions. A three nanosecond MD simulation was conducted using AMBER with long-range electrostatic forces considered using the particle mesh Ewald summation method. The initial model of the Sm binding site region had the central and 3' stem-loops that flanked the Sm site co-axial with one another, and with the single-stranded Sm binding site region ([I] conformation). During the course of the trajectory, the axes of the 3' stem-loop, and later the central stem-loop, became roughly orthogonal from their original anti-parallel orientation. As these conformational changes occurred, the snRNA adopted first an [L] conformation, and finally a [U] conformation. The [U] conformation was more stable than either the [I] or [L] conformations, and persisted for the final 1 ns of the trajectory. Analysis of the structure resulting from the MD simulations revealed the bulged nucleotide, U114, and the mismatched Ag91-G110 base pair provided distinctive structural features that may enhance Sm protein binding. Based on the results of the MD simulation and the available experimental data, we proposed a mechanism for the binding of the Sm protein sub-complexes to the snRNA. In this model, the D1/D2 and E/F/G Sm protein sub-complexes first bind the snRNA in the [U] conformation, followed by conformational re-arrangement to the [I] conformation and binding of the D3/B Sm protein sub-complex.

Base Sequence↗
PubMed1990

Dynamic properties of the first enzymatic reaction steps of porcine pancreatic elastase. How rigid is the active site of the native enzyme? Molecular dynamics simulation.

Two molecular dynamics simulations (100 and 50 ps) of native porcine pancreatic elastase i.e., without bound substrate and with the active site hydrated by a dome of water (630 molecules) have been performed. Dynamical properties of the catalytic tetrad have been examined. While relative conformations of the Asp 102, His 57, and Ser 214 are rather stable in time, the side chain of Ser 195 undergoes several conformational changes. No preferences are observed for the formation of a hydrogen bond between the O gamma-H group (Ser 195) and nitrogen N, (His 57). A cluster of ordered water molecules effectively competes with the H-O gamma group (Ser 195) and thereby prevents the formation of this H bond, which is generally agreed to be crucial for catalysis.

Animals↗
PubMed2002

Modern protein force fields behave comparably in molecular dynamics simulations.

Several molecular dynamics simulations were performed on three proteins--bovine apo-calbindin D9K, human interleukin-4 R88Q mutant, and domain IIA of bacillus subtilis glucose permease--with each of the AMBER94, CHARMM22, and OPLS-AA force fields as implemented in CHARMM. Structural and dynamic properties such as solvent-accessible surface area, radius of gyration, deviation from their respective experimental structures, secondary structure, and backbone order parameters are obtained from each of the 2-ns simulations for the purpose of comparing the protein portions of these force fields. For one of the proteins, the interleukin-4 mutant, two independent simulations were performed using the CHARMM22 force field to gauge the sensitivity of some of these properties to the specific trajectory. In general, the force fields tested performed remarkably similarly with differences on the order of those found for the two independent trajectories of interleukin-4 with CHARMM22. When all three proteins are considered together, no force field showed any consistent trend in variations for most of the properties monitored in the study.

Animals↗
PubMed1989

Superoxide dismutase: fluctuations in the structure and solvation of the active site channel studied by molecular dynamics simulation.

The molecular dynamics (MD) simulation of superoxide dismutase (SOD) in water is carried out for a total of 23 ps. The simulation system is a 26 A sphere centered at the active site of SOD, including 1602 atoms from SOD and 1761 water molecules. There is no gross deviation from the x-ray structure for the average MD structure. The structure and potential fluctuations around the active site are examined. The results provide new insight to the interactions between SOD and its substrate superoxide.

Binding Sites↗