Molecular dynamics simulation of proteins under high pressure: Structure,function and thermodynamics

BackgroundMolecular dynamics (MD) simulation is well-recognized as a powerful tool to investigate protein structure, function, and thermodynamics. MD simulation is also used to investigate high pressure effects on proteins. For conducting better MD simulation under high pressure, the main issues to be addressed are: (i) protein force fields and water models were originally developed to reproduce experimental properties obtained at ambient pressure; and (ii) the timescale to observe the pressure effect is often much longer than that of conventional MD simulations.Scope of reviewFirst, we describe recent developments in MD simulation methodologies for studying the high-pressure structure and dynamics of protein molecules. These developments include force fields for proteins and water molecules, and enhanced simulation techniques. Then, we summarize recent studies of MD simulations of proteins in water under high pressure.Major conclusionsRecent MD simulations of proteins in solution under pressure have reproduced various phenomena identified by experiments using high pressure, such as hydration, water penetration, conformational change, helix stabilization, and molecular stiffening.General significanceMD simulations demonstrate differences in the properties of proteins and water molecules between ambient and high-pressure conditions. Comparing the results obtained by MD calculations with those obtained experimentally could reveal the mechanism by which biological molecular machines work well in collaboration with water molecules.     

Structural phase transition of CdTe: an ab initio study

A constant pressure ab initio MD technique and density functional theory with a generalized gradient approximation (GGA) was used to study the pressure-induced phase transition in zinc-blende CdTe. We found that CdTe undergoes a structural first-order phase transition to $ {\text{I}}\overline 4 {\text{m2}} $ (binary β-tin) tetragonal structure in the constant pressure molecular dynamics simulation at 20 GPa. When the pressure was increased to 50 GPa, the phase of tetragonal structure converted to a new Imm2 orthorhombic structure. These phase transformations were also calculated by using the enthalpy calculations. Transition phases, lattice parameters and bulk properties we attained are comparable with experimental and theoretical data.     

The Structure of Liquid Methanol: A Molecular Dynamics Study Using Three-Site Models

Abstract

The structure of liquid methanol at 298.15 K is investigated by performing molecular dynamics (MD) simulations in NVE ensemble using two 3-site force field models. The simulated structural results are compared with the recent neutron diffraction (ND) results obtained at the partial pair distribution function (pdf) level by employing H/D substitution on the hydroxyl hydrogen, Ho. Overall agreement is found between the simulated and experimental total intermolecular radial distribution functions (rdfs). The ability of the 3-site model simulations to satisfactorily reproduce experimental X—X (X = C, O or H- a methyl hydrogen) intermolecular partial distribution function, dominated by contributions from the methyl group. demonstrates that the methyl group does not participate in any bonding in the liquid. However, a comparison between the simulated and experimental Ho—Ho and X—Ho functions reveals that discrepancies still exist at a quantitative level.     

A Strong to Fragile Transition in a Model of Liquid Silica

Abstract

The transport properties of an ionic model for liquid silica [1] at high temperatures and pressure are investigated using molecular dynamics simulations. With increasing pressure, a clear change from “strong” to “fragile” behaviour (according to Angell's classification of glass-forming liquids) is observed, albeit only on the small viscosity range that can be explored in MD simulations. This change is related to structural changes, from an almost perfect four-fold coordination to an imperfect five or six-fold coordination.     

Investigations of Nematic-Isotropic Transition by Means of Constant Pressure Molecular Dynamics Simulations

Abstract

Constant pressure molecular dynamics simulations, which secure the system to be under hydrostatic pressure, are used to simulate the behavior of liquid crystals consisting of anisotropic molecules with both translational and orientational freedom. In order to investigate to what extent can the properties known to real liquid crystalline phases be explained by the anisotropy of the shape of the molecules alone, the molecular dynamic (MD) simulation uses purely repulsive short-range pair potentials representing soft spherocylinders. A clear change in the microscopic as well as the macroscopic physical properties are observed near the phase transition from nematic liquid crystal to isotropic liquid.     

Molecular Dynamics Simulations for 1:1 Solvent Primitive Model Electrolyte Solutions

Abstract

Molecular dynamics (MD) simulations at constant temperature have been carried out for systems of 1:1 solvent primitive model (SPM) electrolyte solutions. Equilibrium thermodynamics, mean cluster size, self-diffusion coefficients, and collision frequencies were computed to examine the electrostatic effects on the structural and dynamical properties. Coherent ionic cluster motion was deduced from a cluster analysis and from the dependence of the velocity and force autocorrelation functions (FACFs). The resulting MD data for the collision frequencies and self-diffusivities of both ions and hard-spheres were shown to be in good agreement with the theoretical predictions.     

Isobaric and Isothermal Molecular Dynamics Simulations of Diatomic Systems

Abstract

Isobaric molecular dynamics simulations were carried out for diatomic systems using different algorithms available in the literature. Two-centered Lennard-Jones potentials with and without quadrupolar interactions were used. Thermodynamic properties obtained from the isobaric algorithms compared very well with those of an equivalent simulation in the microcanonical ensemble; however, some differences were observed when similar comparisons were carried out for dynamic properties. More specifically, the constant pressure constraint affects the translational dynamics of the system because of the non-negligible differences between the momenta and the instantaneous velocities of the molecules.

Furthermore, the following studies were carried out using isobaric MD simulations: 1. Low temperature spontaneous FCC-orthorhombic (and vice versa) transition of a diatomic system with quadrupolar interactions as a function of the molecular bond length. 2. Effect of quadrupolar interaction on isobaric melting of a model diatomic system. 3. Effect of pressure on melting properties of a model diatomic system with quadrupolar interactions.     

Ab initio and molecular dynamics studies of solid β-HMX: effects of hydrostatic pressure and high temperature

Using first-principles density functional theory and classical molecular dynamics (MD), the structural, electronic and mechanical properties of the energetic material β-HMX have been studied. The crystal structure optimised by the local density approximation calculations compares reasonably with the experimental data. Electronic band structure and density of states indicate that β-HMX is an insulator with a band gap of 3.059 eV. The pressure effect on the crystal structure and physical properties has been investigated in the range of 0–40 GPa. The crystal structure and electronic properties change slightly as the pressure increases from 0 to 2.5 GPa; when the pressure is above 2.5 GPa, further increment of the pressure results in significant changes in crystal structure. There is a larger compression along the b-axis than along the a- and c-axes. Isothermal–isobaric MD simulations on β-HMX were performed in the temperature range of 5–400 K. Phase transition at 360 K, corresponding to a volume interrupt, was found. The computed thermal expansion coefficients show anisotropic behaviour with a slightly larger expansion along the b- and c-axes than along the a-axis. In the temperature range of 5–360 K, β-HMX possesses good plasticity and its stiffness decreases with increasing the temperature.     

Structure of the Sm Binding Site From Human U4 snRNA Derived From a 3 ns PME Molecular Dynamics Simulation

Abstract

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 A₉₁-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.     

Local segmental dynamics of cis-1,4-polybutadiene,polypropylene and polyethylene terephthalate via molecular dynamics simulations

The local segmental dynamics of cis-1,4-polybutadiene, polypropylene and polyethylene terephthalate have been investigated via isothermal-isobaric molecular dynamics simulations. The simulation pressure was 1 atm for all systems, with all simulation temperatures being at least 150 K above the polymer's glass transition temperature. The trajectories have been analysed via autocorrelation functions (ACFs) of chord vectors spanning different number of chain backbone bonds. Inverse Laplace transformations of these ACFs using the CONTIN algorithm afforded the corresponding distribution of relaxation times (DRTs) for the simulated dynamics. All DRTs illustrated a peak on fast timescales corresponding to short length scale segmental motion and a peak at longer timescales corresponding to longer length scale relaxations. A third peak, intermediate between the fast and slow processes, appears as the relaxation of chord vectors spanning increasing number of backbone bonds is considered. The temperature dependence of the relaxation dynamics is also investigated.     

Molecular Dynamics Study of Li2SiO3 in the Liquid and Glassy States

Abstract

Molecular dynamics simulation (MD) has been carried out for Li₂SiO₃ in the molten and glassy states. The parameters of the pair potential functions were determined by a trial and error method so that the results of X-ray diffraction analysis could be well reproduced.

The changes in the structure and dynamic properties accompanied by lowering temperature revealed that the glass transition of this simulated system occurred between 973 and 700 K. The ratio of the bridging oxygens to non-bridging oxygens was nearly constant over the investigated temperature range, while a small change in the pattern of branching of the -Si-O-framework was found. The second peaks in the pair correlation functions g_Si-O(r) and g_Si-Si(r) split at lower temperature. These splittings suggest that the motion changing the relative orientations of two neighboring SiO₄ units may be nearly frozen at lower temperature.     

On the temperature and pressure dependence of a range of properties of a type of water model commonly used in high-temperature protein unfolding simulations

Molecular dynamics simulations of protein folding and unfolding are often carried out at temperatures (400-600 K) that are much higher than physiological or room temperature to speed up the (un)folding process. Use of such high temperatures changes both the protein and solvent properties considerably, compared to physiological or room temperature. Water models designed for use in conjunction with biomolecules, such as the simple point charge (SPC) model, have generally been calibrated at room temperature and pressure. To determine the distortive effect of high simulation temperatures on the behavior of such "room temperature" water models, the structural, dynamic, and thermodynamic properties of the much-used SPC water model are investigated in the temperature range from 300 to 500 K. Both constant pressure and constant volume conditions, as used in protein simulations, were analyzed. We found that all properties analyzed change markedly with increasing temperature, but no phase transition in this temperature range was observed.     

The calcium binding proteins calbindin,parvalbumin, and calretinin have specific patterns of expression in the gray matter of cat spinal cord

Calcium binding proteins (CBPs) regulate intracellular levels of calcium (Ca²⁺) ions. CBPs are particularly interesting from a morphological standpoint, because they are differentially expressed in certain sub-populations of cells in the nervous system of various species of vertebrate animals. However, knowledge on the cellular regulation governing such cell-specific CBP expression is still incomplete. In this work on the L7 segment of the cat spinal cord, we analyzed the localization and morphology of neurons expressing the CBPs calbindin-28 KD (CB), parvalbumin (PV), and calretinin (CR), and co-expressing CB and PV, CB and CR, and PV and CR. Single CBP-positive (⁺) neurons showed specific distributions: (1) CB was present in small neurons localized in laminae I, II, III and X, in small to medium size neurons in laminae III–VI, and in medium to large neurons in laminae VI–VIII; (2) PV was present in small size neurons in laminae III and IV and in medial portions of laminae V and VI, medium neurons and in lamina X at the border with lamina VII, in medium to large neurons in laminae VII and VIII; (3) CR labeling was detected in small size neurons in laminae I, II, III and VIII, in medium to large size neurons in laminae I and III–VII, and in small to medium size neurons in lamina X. Double labeled neurons were a small minority of the CBP⁺ cells. Co-expression of CB and PV was seen in 1 to 2% of the CBP⁺ cells, and they were detected in the ventral and intermediate portions of lamina VII and in lamina X. Co-localization of CB and CR was present in 0.3% of the cells and these cells were localized in lamina II. Double labeling for PV and CR occurred in 6% of the cells, and the cells were localized in ventral part of lamina VII and in lamina VIII. Overall, these results revealed distinct and reproducible patterns of localization of the neurons expressing single CBPs and co-expressing two of them. Distinct differences of CBP expression between cat and other species are discussed. Possible relations between the cat L7 neurons expressing different CBPs with the neurons previously analyzed in cat and other animals are suggested.     

Changes in desiccation resistance during development in the millipede Polydesmus angustus

Water loss at increasing temperature in dry air (< 5% r.h.) was measured for the eight stadia of Polydesmus angustus Latzel (Diplopoda, Polydesmida: Polydesmidae). Instantaneous rates of water loss, expressed as percentages of original body water, were calculated at 20, 25 and 30°C. At each temperature, the rate of water loss varied greatly among stadia, decreasing between 15‐ and 18‐fold from stadium I to stadium VII, and then significantly increasing from stadium VII to stadium VIII (adult). In all stadia, the rate of water loss increased with rising temperature, but the temperature effect was much more pronounced in juveniles than in larger stadia. The threshold temperature of heat stupor, which was measured from stadium IV onwards, increased significantly during development, from 35.6°C in stadium IV to 39.5°C in adults. Survival at 20°C and 76% r.h. varied as could be expected from the water loss rates in dry air, survival time increasing from stadium I to stadium VII and then decreasing from stadium VII to the adult stage. The maximum tolerable water loss, estimated for stadia V, VII and adults, did not change significantly among stadia (mean: 47% of the original water content), suggesting that survival times under desiccating conditions depended primarily on the rates of water loss. The relevance of the results in terms of summer survival under natural conditions is discussed, and it is concluded that juvenile mortality could be substantial in the field. This is important for understanding the adaptive value of cohort‐splitting in P. angustus.     

Molecular Dynamics Simulations of Complexes Between Wild-Type and Mutant Anthrax Protective Antigen Variants and a Model Anthrax Toxin Receptor

Abstract

Bacillus anthracis, a spore-forming infectious bacterium, produces a toxin consisting of three proteins: lethal factor (LF), edema factor (EF), and protective antigen (PA). LF and EF possess intracellular enzymatic functions, the net effect of which is to severely compromise host innate immunity. During an anthrax infection PA plays the critical role of facilitating entry of both EF and LF toxins into host cell cytoplasm. Crystal structures of all three of the anthrax toxins have been determined, as well as the crystal structure of the (human) von Willebrand factor A (integrin VWA/I domain)—an anthrax toxin receptor. A theoretical structure of the complex between VWA/I and PA has also been reported. Here we report on the results of 1,000 psec molecular dynamics (MD) simulations carried out on complexes between the Anthrax Protective Antigen Domain 4 (PA-D4) and the von Willebrand Factor A (VWA/I). MD simulations (using Insight II software) were carried out for complexes containing wildtype (WT) PA-D4, as well as for complexes containing three different mutants of PA-D4, one containing three substitutions in the PA-D4 “small loop” (residues 679–693) (D683A/L685E/Y688C), one containing a single substitution at a key site at the PA-D4—receptor interface (K679A) and another containing a deletion of eleven residues at the C-terminus of PA (A724–735). All three sets of PA mutations have been shown experimentally to result in serious deficiencies in PA function. Our MD results are consistent with these findings. Major disruptions in interactions were observed between the mutant PA-D4 domains and the anthrax receptor during the MD simulations. Many secondary structural features in PA-D4 are also severely compromised when VWA complexes with mutant variants of PA-D4 are subjected to MD simulations. These MD simulation results clearly indicate the importance of the mutated PA-D4 residues in both the “small loop” and at the carboxyl terminus in maintaining a PA conformation that is capable of effective interaction with the anthrax toxin receptor.     

Trifonov's Meta-Definition of Life

Abstract

We present here results on 260 pico seconds (ps) molecular dynamics (MD) simulation of substance P (SP) in hydrated bilayer of dimyristoyl phosphatidyl choline (DMPC) (39 molecules of DMPC with 776 water molecules). 260 ps MD simulation has been carried out in 0.001 ps time interval with united atom force field, using AMBER 4.0 package. Non bonded pair list was updated every 20 cycles using 12.5 Å cut off distance. Analysis of MD data is done using our package ANALMD. The obtained models are presented using graphics package RASMOL. All simulations, analysis of MD data and graphics is done on INDIGO-2, R-4400 extreme graphics work station. Our results show no systematic change in order parameter, but reduction in transfraction of the chain torsional angles, compared to our earlier results on MD simulation on hydrated DMPC bilayer without SP. C-terminal and central peptide residues adopt partial helical conformation. Helix type as classified on the basis of H-bonds is between a and 3₁₀. The peptide backbone shows flexibility during heating runs. Later, it is stabilized and there was not much change in the spatial position of the backbone. Lipid matrix serves the role of immobilization of the peptide backbone in a preferred conformation.     

Ab Initio Molecular Dynamics for Simple Liquid Metals Based on the Hypernetted-Chain Approximation

Abstract

We present an ab initio molecular dynamics (MD) method for simple liquid metals based on the quantal hypernetted-chain (QHNC) theory derived from exact expressions for radial distribution functions (RDF's) of the electron-ion model for liquid metals. In our method based on the QHNC equations, the classical MD is performed repeatedly to determine a self-consistent effective interionic potential, which depends on the ion-ion RDF of the system. This resultant effective ionic potential is obtained to be consistent with the density distribution of a pseudoatom and the electron-ion RDF, as well as the ion-ion RDF and the ion-ion bridge function, which are determined exactly as a result of the repeated MD simulation. We have applied this QHNC-MD method for Li, Na, K, Rb, and Cs near the melting temperature using upto 16,000 particles for the MD simulation. It is found that the convergence of the effective interionic potential is fast enough for practical applications; typically two MD runs are enough for convergence of the effective ionic potential within accuracy of 3 to 4 digits. Furthermore the resultant static structure factor is in excellent agreement with experimental data of X-ray and/or neutron scatering.     

Examination of structural stability and phase transitions in constant-pressure first-principles molecular dynamics simulations

Constant-pressure first-principles molecular dynamics (FPMD) simulation is a powerful tool for investigations of structures in crystals. However, it needs enourmous computations so that highly accurate calculations for electronic states cannot be employed at present. In this report, we examined the reliability and applicability of constant-pressure FPMD in the study of structural properties under this limitation. Crystalline silicon was employed as a benchmark to perform constant-pressure FPMD simulations (with a deformable simulation cell). It is found that, in high pressure (metallic) phases, crystalline symmetry is broken with the present simulation conditions. Several structural transformations were realized by compression and decompression, but they are not entirely consistent with experiment. We discuss this discrepancy and conclude that the number of k point sampling in the Brillouin zone is crucial. It is recommended that constant-pressure FPMD is employed to explore candidate structures for unknown solid phases at present computational resources.     

Molecular Dynamics Studies of Sequence-directed Curvature in Bending Locus of Trypanosome Kinetoplast DNA

Abstract

The macroscopic curvature induced in the double helical B-DNA by regularly repeated adenine tracts (A-tracts) plays an exceptional role in structural studies of DNA because this effect presents the most well documented example of sequence specific conformational modulations. Recently, a new hypothesis of its physical origin has been put forward. According to it, the intrinsic bends in B-DNA may represent one of the consequences of the compressed frustrated state of its backbone. The compressed backbone hypothesis agrees with many data and explains some controversial experimental observations. The original arguments of this theory came out from MD simulations of a DNA fragment with a strong bending propensity. Its sequence, however, was not experimental. It was constructed empirically so as to maximize the magnitude of bending in calculations. To make sure that our computations reproduce the experimental effect we carried out similar simulations with an A-tract repeat of a natural base pair sequence found in a bent locus of a minicircle DNA. We demonstrate spontaneous development of static curvature in the course of MD simulations excluding any initial bias except the base pair sequence. Its direction and magnitude agree with experimental estimates. The results confirm earlier qualitative conclusions and agree with the hypothesis of a compressed backbone as the origin of static bending in B-DNA.