Studies of ice melting using molecular dynamics

In this paper, the melting of ice 1h is studied using molecular dynamics (MD). Common potential functions employed in the MD simulations include SPC/E, TIP4P, TIP5P, TIP4/ice and TIP5P/E. We first conducted melting of ice bulks and then studied the melting speed of the ice/water interface during ice melting. It is found that various potentials result in similar ice-melting phenomena. The result is compared with the analytical solution for phase change problem. We also studied size effects and temperature gradient effects on ice melting.     

Long time dynamics of Met-enkephalin: comparison of explicit and implicit solvent models

Met-enkephalin is one of the smallest opiate peptides. Yet, its dynamical structure and receptor docking mechanism are still not well understood. The conformational dynamics of this neuron peptide in liquid water are studied here by using all-atom molecular dynamics (MD) and implicit water Langevin dynamics (LD) simulations with AMBER potential functions and the three-site transferable intermolecular potential (TIP3P) model for water. To achieve the same simulation length in physical time, the full MD simulations require 200 times as much CPU time as the implicit water LD simulations. The solvent hydrophobicity and dielectric behavior are treated in the implicit solvent LD simulations by using a macroscopic solvation potential, a single dielectric constant, and atomic friction coefficients computed using the accessible surface area method with the TIP3P model water viscosity as determined here from MD simulations for pure TIP3P water. Both the local and the global dynamics obtained from the implicit solvent LD simulations agree very well with those from the explicit solvent MD simulations. The simulations provide insights into the conformational restrictions that are associated with the bioactivity of the opiate peptide dermorphin for the delta-receptor.     

Molecular dynamics simulation of the graphene–water interface: comparing water models

In this work, different water models (i.e. SPC/E, TIP3P, TIP4P/2005, TIP5P, SPC/Fw, TIP4P/2005f and SWM4_DP) are implemented to simulate water on neutral, negatively charged and positively charged graphene. In all cases ambient conditions are considered. Structural and dynamical properties for water are calculated to quantify the differences among various water models. The results show that SPC/E, TIP4P/2005, SPC/Fw, TIP4P/2005f and SWM4_DP water models yield a similar structure for interfacial water on graphene, whether it is neutral, negatively charged or positively charged. TIP5P is the model whose predictions for the structure of the interface deviate the most from those of the other models. Although qualitatively the results are for the most part similar, a large quantitative variation is observed among the dynamical properties predicted when various water models are implemented. Although experimental data are not available to discriminate the most/least accurate of the model predictions, our results could be useful for comparing results for interfacial water obtained implementing different models. Such critical comparison will benefit practical applications such as the development of energy-storage and water-desalination devices (e.g. electric double-layer capacitors), among others.     

A probabilistic approach for estimating water permeability in pressure-driven membranes

A probabilistic approach is proposed to estimate water permeability in a cellulose triacetate (CTA) membrane. Water transport across the membrane is simulated in reverse osmosis mode by means of non-equilibrium molecular dynamics (MD) simulations. Different membrane configurations obtained by an annealing MD simulation are considered and simulation results are analyzed by using a hierarchical Bayesian model to obtain the permeability of the different membranes. The estimated membrane permeability is used to predict full-scale water flux by means of a process-level Monte Carlo simulation. Based on the results, the parameters of the model are observed to converge within 5-ns total simulation time. The results also indicate that the use of unique structural configurations in MD simulations is essential to capture realistic membrane properties at the molecular scale. Furthermore, the predicted full-scale water flux based on the estimated permeability is within the same order of magnitude of bench-scale experimental measurement of 1.72×10^?5 m/s.     

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.     

Simulation of protein diffusion: a sensitive probe of protein–solvent interactions

Aqueous solutions of Candida antarctica lipase B (CALB) were simulated considering three different water models (SPC/E, TIP3P, TIP4P) by a series of molecular dynamics (MD) simulations of three different box sizes (L = 9, 14, and 19 nm) to determine the diffusion coefficient, the water viscosity and the protein density. The protein–water systems were equilibrated for 500 ns, followed by 100 ns production runs which were analysed. The diffusional properties of CALB were characterized by the Stokes radius (R_S), which was derived from the diffusion coefficient and the viscosity. R_S was compared to the geometric radius (R_G) of CALB, which was derived from the protein density. R_S and R_G differed by 0.27 nm for SPC/E and by 0.40 and 0.39 nm for TIP3P and TIP4P, respectively, which characterizes the thickness of the diffusive hydration layer on the protein surface. The simulated hydration layer of CALB resulted in agreement with those experimentally determined for other seven different proteins of comparable size. By avoiding the most common pitfalls, protein diffusion can be reliably simulated: simulating different box sizes to account for the finite size effect, equilibrating the protein–water system sufficiently, and using the complete production run for the determination of the diffusion coefficient.     

Computer Simulation of the Dielectric Properties of Liquid Water

Abstract

Monte Carlo simulations of water in the NVT ensemble using three models (SPC, TIP4P and TIPS2) are reported. The internal energy, dielectric constant, and the site-site radial distribution functions of liquid water (temperature 300 K and mass density 1 gm cc^?1) were calculated and compared with experiment. It was found that of the three intermolecular potential models, SPC gives the best dielectric constant. Since SPC also yields acceptable results for the energy and structure, it is judged to be the best among the three models studied.     

Investigation of conformational mobility of insulin superfamily peptides: Use of SPC/E and TIP4P water models

A comparative analysis of the two most widely used water models, SPC/E and TIP4P, was carried out. The applicability of the models for studying the conformational mobility of peptides of the insulin superfamily, including proinsulin and insulin-like growth factors (IGF1 and IGF2), was assessed. It was demonstrated that, in the case of both water models, the root-mean-square deviations and the gyration radii tend to exist in the anti-phase; their values only reached a plateau after 9000 ps in the case of IGF1. Additionally, it was shown that, despite maintaining a general type of insulin-like packing structure, the secondary structures were somewhat different when SPC/E and TIP4P were used. These differences could affect the overall dynamics of molecules, as well as their ability to adopt the conformation required to bind with conjugate receptors. We conclude that several, not one, water models should be used to investigate the conformational mobility of peptides.     

Examination of the quality of various force fields and solvation models for the equilibrium simulations of GA88 and GB88

Elucidating the relationship between sequence and conformation is essential for the understanding of functions of proteins. While sharing 88 % sequence identity and differing by only seven residues, GA88 and GB88 have completely different structures and serve as ideal systems for investigating the relationship between sequence and function. Benefiting from the continuous advancement of the computational ability of modern computers, molecular dynamics (MD) simulation is now playing an increasingly important role in the study of proteins. However, the reliability of MD simulations is limited by the accuracy of the force fields and solvent model approximations. In this work, several AMBER force fields (AMBER03, AMBER99SB, AMBER12SB, AMBER14SB, AMBER96) and solvent models (TIP3P, IGB5, IGB7, IGB8) have been employed in the simulations of GA88 and GB88. The statistical results from 19 simulations show that GA88 and GB88 both adopt more compact structures than the native structures. GB88 is more stable than GA88 regardless of the force fields and solvent models utilized. Most of the simulations overestimated the salt bridge interaction. The combination of AMBER14SB force field and IGB8 solvent model shows the best overall performance in the simulations of both GA88 and GB88. AMBER03 and AMBER12SB also yield reasonable results but only in the TIP3P explicit solvent model.     

Energetics of water proton configurations in gas hydrates: comparison of various water models

The total interaction energies for a large number of water proton configurations in the unit cell of hydrate structure I consisting of 46 molecules are compared for qualitatively different water models, such as SPC/E, TIP4P, TIP5P, TIP 3f and AMOEBA. All calculations were carried out using the TINKER molecular modelling package. The Ewald summation method with metallic tin-foil boundary conditions is used to account for long-range electrostatic interactions. It was established that there is a high correlation between the energies calculated using the five water models (interaction potentials). The average correlation coefficient for all pairs of potentials is equal to 0.91. Analogous calculations were carried out to evaluate the consistency of the different water models with respect to a new property of the ice-like system: the hydrogen-bond-reversal asymmetry. It was established that, for all water models, there is relatively high correlation between the energy differences for proton configurations with opposite direction of all hydrogen bonds. In this case, the average correlation coefficient is 0.77. Data for the TIP4P potential differ noticeably from the others, especially owing to the variation in the total interaction energy. The validity and usefulness of simple discrete models of inter-molecular interactions are discussed.     

Molecular Dynamics Simulation of Limiting Conductance for Li + Ion in Supercritical Water using Polarizable Models

We report results of molecular dynamics simulations of the limiting conductance of Li + ion in ambient water and in supercritical water using polarizable models for water and Li + . The limiting conductances of Li + in ambient water calculated from mean square displacement (MSD) using four points transferable intermolecular potential model (TIP4P), extended simple point charge model (SPC/E), and revised polarizable model 1 (RPOL1) are larger than the experimental value. The behavior of the limiting conductance of Li + in supercritical water using the RPOL models results in good agreement with experimental results for the limiting conductance of LiCl. The agreement of the RPOL1 model with the experimental results is much better than the RPOL2 model in the higher-density regime, whereas that of the RPOL2 model is much better than the RPOL1 model in the lower-density regime. Using the RPOL models (in contrast to the SPC/E model), the number of hydration water molecules around Li + is the dominating contributor to the limiting conductance in the higher-density regime. In agreement with the SPC/E model, the interaction strength between Li + and the hydration water molecules is a non-factor in the lower-density region since the potential energy per hydration water molecule decreases with decreasing water density at the lowest water densities.     

A Robust Water Potential Parameterisation

Abstract

We compare molecular dynamics simulation results for the properties of liquid water predicted by four novel water potential models. These models are designed as a combination of parameters taken from the dedicated but brittle TIP3P water potential, and the more flexible but less accurate parameterisations such as the Dreiding and Universal force fields. We find that a hybrid of Dreiding and TIP3P delivers the best results, yielding a density, diffusion coefficient and radial distribution function in good agreement with experiment, performing in some respects even better than the dedicated reference TIP3P model. Another Dreiding based force field predicts semi-quantitative results for the water structure and dynamics while the Universal force field based models are incapable of simulating a condensed phase of water at all, continuing to expand indefinitely. These observations are useful for selecting and designing robust water force field parameterisations that can be used for general simulation purposes.     

Molecular dynamics simulation of a decasaccharide fragment of heparin in aqueous solution

Molecular dynamics (MD) simulations on heparin-water-sodium systems were carried out in order to establish a simulation protocol able to represent heparin solution conformation under physiological conditions. Atomic charges suitable for heparin oligosaccharides were obtained from ab initio quantum-mechanical computations, at the 6-31G(**) level. The GROMACS forcefield, the SPC, and SPC/E water models were employed. Also heparin was simulated with IdoA residues in 1C(4) or 2S(0) conformational states. The results of the performed MD simulations are in agreement with the available experimental data, suggesting that this approach can be applied for the study of heparin interactions with its target proteins and thus play a role in the development of new antithrombotic agents.     

The Application of the Reaction-Field Method to the Calculation of Dielectric Constants

Abstract

The behaviour of the popular TIP3P water model has been investigated using both molecular dynamics and Monte Carlo simulation procedures. Long-range electrostatic interactions were included through a reaction-field treatment, and the nonbonded interactions were either truncated at the cutoff distance, or smoothly scaled to zero using a switching function. The thermodynamic observables, and in particular the dipole-dipole correlation functions, are found to differ between the two simulation techniques if a rigid nonbonded cutoff is applied. However, use of a switching function gives exact agreement between the simulation methodologies. This difference is ascribed to the effect of energy pumping in the molecular dynamics simulations, and suggests that dielectric constants calculated using this simulation method with the fluctuation procedure in conjunction with a reaction field should be reappraised. Thus the Monte Carlo simulation procedure offers a number of intrinsic advantages over molecular dynamics for the calculation of dielectric constants with a reaction field. The most precise value for the dielectric constant of TIP3P is calculated to be 102 ± 3 at 298 K.     

Structural Characterization of N-WASP Domain V Using MD Simulations with NMR and SAXS Data

Because of their large conformational heterogeneity, structural characterization of intrinsically disordered proteins (IDPs) is very challenging using classical experimental methods alone. In this study, we use NMR and small-angle x-ray scattering (SAXS) data with multiple molecular dynamics (MD) simulations to describe the conformational ensemble of the fully disordered verprolin homology domain of the neural Aldrich syndrome protein involved in the regulation of actin polymerization. First, we studied several back-calculation software of SAXS scattering intensity and optimized the adjustable parameters to accurately calculate the SAXS intensity from an atomic structure. We also identified the most appropriate force fields for MD simulations of this IDP. Then, we analyzed four conformational ensembles of neural Aldrich syndrome protein verprolin homology domain, two generated with the program flexible-meccano with or without NMR-derived information as input and two others generated by MD simulations with two different force fields. These four conformational ensembles were compared to available NMR and SAXS data for validation. We found that MD simulations with the AMBER-03w force field and the TIP4P/2005s water model are able to correctly describe the conformational ensemble of this 67-residue IDP at both local and global level.     

Water in channel-like cavities: structure and dynamics.

Ion channels contain narrow columns of water molecules. It is of interest to compare the structure and dynamics of such intrapore water with those of the bulk solvent. Molecular dynamics simulations of modified TIP3P water molecules confined within channel-like cavities have been performed and the orientation and dynamics of the water molecules analyzed. Channels were modeled as cylindrical cavities with lengths ranging from 15 to 60 A and radii from 3 to 12 A. At the end of the molecular dynamics simulations water molecules were observed to be ordered into approximately concentric cylindrical shells. The waters of the outermost shell were oriented such that their dipoles were on average perpendicular to the normal of the wall of the cavity. Water dynamics were analyzed in terms of self-diffusion coefficients and rotational reorientation rates. For cavities of radii 3 and 6 A, water mobility was reduced relative to that of simulated bulk water. For 9- and 12-A radii confined water molecules exhibited mobilities comparable with that of the bulk solvent. If water molecules were confined within an hourglass-shaped cavity (with a central radius of 3 A increasing to 12 A at either end) a gradient of water mobility was observed along the cavity axis. Thus, water within simple models of transbilayer channels exhibits perturbations of structure and dynamics relative to bulk water. In particular the reduction of rotational reorientation rate is expected to alter the local dielectric constant within a transbilayer pore.     

Water and deuterium oxide permeability through aquaporin 1: MD predictions and experimental verification

Determining the mechanisms of flux through protein channels requires a combination of structural data, permeability measurement, and molecular dynamics (MD) simulations. To further clarify the mechanism of flux through aquaporin 1 (AQP1), osmotic p(f) (cm(3)/s/pore) and diffusion p(d) (cm(3)/s/pore) permeability coefficients per pore of H(2)O and D(2)O in AQP1 were calculated using MD simulations. We then compared the simulation results with experimental measurements of the osmotic AQP1 permeabilities of H(2)O and D(2)O. In this manner we evaluated the ability of MD simulations to predict actual flux results. For the MD simulations, the force field parameters of the D(2)O model were reparameterized from the TIP3P water model to reproduce the experimentally observed difference in the bulk self diffusion constants of H(2)O vs. D(2)O. Two MD systems (one for each solvent) were constructed, each containing explicit palmitoyl-oleoyl-phosphatidyl-ethanolamine (POPE) phospholipid molecules, solvent, and AQP1. It was found that the calculated value of p(f) for D(2)O is approximately 15% smaller than for H(2)O. Bovine AQP1 was reconstituted into palmitoyl-oleoyl-phosphatidylcholine (POPC) liposomes, and it was found that the measured macroscopic osmotic permeability coefficient P(f) (cm/s) of D(2)O is approximately 21% lower than for H(2)O. The combined computational and experimental results suggest that deuterium oxide permeability through AQP1 is similar to that of water. The slightly lower observed osmotic permeability of D(2)O compared to H(2)O in AQP1 is most likely due to the lower self diffusion constant of D(2)O.     

Probing structural features of Alzheimer's amyloid-β pores in bilayers using site-specific amino acid substitutions

A current hypothesis for the pathology of Alzheimer's disease (AD) proposes that amyloid-β (Aβ) peptides induce uncontrolled, neurotoxic ion flux across cellular membranes. The mechanism of ion flux is not fully understood because no experiment-based Aβ channel structures at atomic resolution are currently available (only a few polymorphic states have been predicted by computational models). Structural models and experimental evidence lend support to the view that the Aβ channel is an assembly of loosely associated mobile β-sheet subunits. Here, using planar lipid bilayers and molecular dynamics (MD) simulations, we show that amino acid substitutions can be used to infer which residues are essential for channel structure. We created two Aβ(1-42) peptides with point mutations: F19P and F20C. The substitution of Phe19 with Pro inhibited channel conductance. MD simulation suggests a collapsed pore of F19P channels at the lower bilayer leaflet. The kinks at the Pro residues in the pore-lining β-strands induce blockage of the solvated pore by the N-termini of the chains. The cysteine mutant is capable of forming channels, and the conductance behavior of F20C channels is similar to that of the wild type. Overall, the mutational analysis of the channel activity performed in this work tests the proposition that the channels consist of a β-sheet rich organization, with the charged/polar central strand containing the mutation sites lining the pore, and the C-terminal strands facing the hydrophobic lipid tails. A detailed understanding of channel formation and its structure should aid studies of drug design aiming to control unregulated Aβ-dependent ion fluxes.     

Molecular dynamics simulations of membrane proteins

Membrane proteins control the traffic across cell membranes and thereby play an essential role in cell function from transport of various solutes to immune response via molecular recognition. Because it is very difficult to determine the structures of membrane proteins experimentally, computational methods have been increasingly used to study their structure and function. Here we focus on two classes of membrane proteins—ion channels and transporters—which are responsible for the generation of action potentials in nerves, muscles, and other excitable cells. We describe how computational methods have been used to construct models for these proteins and to study the transport mechanism. The main computational tool is the molecular dynamics (MD) simulation, which can be used for everything from refinement of protein structures to free energy calculations of transport processes. We illustrate with specific examples from gramicidin and potassium channels and aspartate transporters how the function of these membrane proteins can be investigated using MD simulations.