Molecular Dynamics Simulation of Hexamine and Suberic Acid

In order to perform a molecular dynamics (MD) simulation of the incommensurate crystalline structure hexamethylenetetramine suberate (C 6 H 12 N 4 )(HOOC-(CH 2 ) 6 -COOH), we present in a first step the separate simulations of the crystalline structure of each of the two pure components, hexamethylenetetramine (HMT) and suberic acid. The domain decomposition parallel MD program ddgmq is used for this purpose. A second-generation consistent force field (CFF91) is employed to describe the interactions between atoms. Starting from experimental crystal structures, both pure components were heated from low to high temperatures. Our MD results show that the HMT system can be well represented by CFF91. In the case of suberic acid the layered structure of the crystal is largely preserved although deviations in the unit cell lengths from the experimental values are ～10%. Rather than attempt a complex re-parametrisation of CFF91 we chose to impose a fixed compensating external pressure tensor to correct for the deficiencies of the chosen force field. After optimising this compensating external pressure tensor at one temperature we find that experimental lattice constants and angles can be well reproduced over a range of temperatures.     

Molecular Dynamics Simulation of Collective Motions in Binary Liquids

Collective dynamic properties of different kind of binary liquid mixtures have been investigated by molecular dynamics simulation. The study includes both the longitudinal and the transverse current spectra in simple liquid alloys, 1:1 molten salts and liquid binary mixtures of neutral particles with an ionic-like structure. These systems were chosen as representative of binary liquids with different static structures in order to analyse the effects of structural ordering on the mechanisms of dynamic collective properties. The effect of the mass asymmetry between the two species in the mixture has been also discussed from the results for two different mass ratios for each kind of structure. Two length scales have been considered. On the one hand, the hydrodynamic scale (low wave numbers), where the modes for the partial currents of the two species are characterised by very close frequencies. On the other hand, the molecular scale (higher wave numbers), where the characteristic frequencies for the two species show noticeable differences. Vibrational concentration current modes (optic modes) have been found in neutral mixtures though their influence is rather weak, being the collective dynamic properties of this kind of systems dominated by the mass current modes (acoustic modes). On the contrary, in mixtures of charged particles such as molten salts the contribution of the concentration (charge) currents to the collective dynamics is important and optic modes can be characterised by a well-defined frequency for a wide range of wave numbers. It has been observed that heavy particles have a more relevant role on the mass current correlations whereas light particles play a dominant role on the concentration current correlations. The overall results for the three kinds of liquid mixtures analysed in this paper show that both the longitudinal and transverse current spectra are little dependent on the static structure of the system whereas marked differences are revealed when the particles in the system are either neutral or carry an electric charge.     

Structural and Dynamical Studies of Humanin in Water and TFE/Water Mixture: A Molecular Dynamics Simulation

Summary

Proline-rich peptides are known to adopt preferentially the extended polyproline II (PPII) helical conformation, which is involved in several protein-protein recognition events. By resorting to molecular modelling techniques, we wished to investigate the extent to which PPII helices could be used for the formation of isohelical peptide-DNA complexes leading to the selective recognition of the major groove of B-DNA. For that purpose, we have grafted to a cationic intercalator, 9-amino-acridine, an oligopeptide having the sequence: Pro-Arg-Pro-Pro-Arg-Pro-Pro-Arg-Pro-Pro-Asp-Pro-Pro. Each residue in the sequence was set in the D configuration, to prevent enzymatic hydrolysis, and each Arg residue was designed to target O6/N7 of a guanine base following the intercalation site. The Asp residue was designed to target a cytosine base, whilst simultaneously forming a bidentate complex with the Arg three residues upstream. Energy-minimization, using the JUMNA procedure, led to the following conclusions: 1) major groove binding is favoured over minor groove or exclusive binding to the phosphates by large energy differences, of over 50 and 90 kcal/mole, respectively; 2) the two best bound sequences are those having three successive guanine bases on the same DNA strand, immediately adjacent to the intercalation site. Sequence d(CGGGC G), encountered in the Primer Binding Site of the HIV retrovirus, thus ranks amongst the best-bound sequences; 3) replacement of an individual guanine amongst the three ones upstream of the intercalation site, by an adenine base, weakens by > 6 kcal/mole the binding energetics; 4) the conformational rigidity of the DNA-bound PPII helix should enable for a modulation of the base sequence selectivity, by appropriate replacements of the Arg and Asp residues. Thus sequence CGGCAAG, also encountered in the HIV genome, could be targeted by an oligopeptide having the sequence Pro-Arg-Pro-Pro-Asp-Pro-Pro- Asn-Pro-Pro-Asn-Pro-Pro-Arg-Ala.     

Multiple Time Step Brownian Dynamics for Long Time Simulation of Biomolecules

We report a multiple time step algorithm applied to an atomistic Brownian dynamics simulation for simulating the long time scale dynamics of biomolecules. The algorithm was based on the original multiple time step method; a short time step was used to keep faster motions in local equilibrium. When applied to a 28-mer # # ! folded peptide, the simulation gave stable trajectories and the computation time was reduced by a factor of 160 compared to a conventional molecular dynamics simulation using explicit water molecules. We applied it for the folding simulation of a 13-mer ! -helical peptide, giving a successful folding simulation. These results indicate that the Brownian dynamics with the multiple time step algorithm is useful for studies of biomolecular motions by long time simulation.     

嗜温冷休克蛋白力致去折叠研究

嗜温冷休克蛋白拥有一个由五个β股形成的反平行β桶结构,目前已被用于蛋白质去折叠的研究。当使用机械力对嗜温冷休克蛋白进行拉伸研究时,发现嗜温冷休克蛋白的去折叠过程具有明显的中间态。在常速和常力两种情况下对嗜温冷休克蛋白进行拉伸分子动力学模拟,发现其在两种情况下具有相同的去折叠次序,即C端β片层首先去折叠,随后N端β片层去折叠;同时这两种模拟都表现出明确的中间态。研究结果表明,嗜温冷休克蛋白抵抗外力作用除了依赖链间氢键外,分子内的静电相互作用也发挥着重要的作用。     

Molecular Dynamics Simulation Study of the Interaction of Piscidin 1 with DPPC Bilayers: Structure-Activity Relationship

Abstract

To study structure-activity relationship of antimicrobial peptides and to design novel antimicrobial peptides with selectivity for bacterial cells, we have performed molecular dynamics simulations of the interaction of Piscidin (Pis1) and its two analogues (Pis1-AA and Pis1-PG) with dipalmitoylphosphatidylcholine (DPPC) bilayer through 45 ns. Our results inform us of the detailed location and orientation of the peptide with respect to the bilayer as well as provide about hydrogen-bond-formation patterns and electrostatics interactions. Simulations show that Pis1 and Pis-AA form the most hydrogen bonds and Pis-PG forms the fewest hydrogen bonds with lipid. Thus, Pis1 and Pis-AA should have stronger interactions with the lipid head group when compared to Pis-PG. Experimental studies have shown that Pis1 and Pis1-AA have a high antimicrobial and hemolytic activities, and Pis1-PG has low hemolytic activity while keeps potent antimicrobial activity. Our results complement the previous experimental studies. According to our MD results and previous experimental studies, Pis1 and Pis1-AA are more effective at the zwitterionic bilayer comparing Pis1-PG. These properties of Pis1-PG could be accordance with its low hemolytic activities.     

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.     

Classical Molecular Dynamics Simulation of Kappa Squared Factor in Resonance Energy Transfer for Linear Dipole Models

Molecular dynamics simulations of linear models interacting through a dipolar Kihara intermolecular potential are presented. Molecular orientation correlations are used to calculate the orientational factor kappa squared in the resonance energy transfer (RET) as a function of the intermolecular separation. The distance, R 0 (2/3), at which the simulated systems show an isotropic behavior is calculated and an analysis of the dependence of R 0 (2/3) on microscopic properties (molecular aspect ratio and dipole moment) as well on thermodynamics (temperature and density) is presented. An explanation of the use of metallic cations as probes in RET is given and some relations of our models with biological molecules are pointed out.     

Ewald Summation in the Molecular Dynamics Simulation of Large Ionic Systems

Abstract

The accuracy and efficiency of the direct Ewald summation are discussed in terms of the size of a Molecular Dynamics (MD) ionic system and the ranges of the r-space and q-space summations. The dependence of the convergence parameter α on the size of the system and on the choice of cut-off radius for the short-range potential is given. The possibility of neglecting the q-space term for large ionic systems is discussed in terms of the accuracy and efficiency of the simulation.     

Lipid Membrane Structure and Dynamics Studied by All-Atom Molecular Dynamics Simulations of Hydrated Phospholipid Bilayers

Abstract

The structure and dynamics of phosphatidylcholine bilayers are examined by reviewing the results of several nanoseconds of molecular dynamics simulations on a number of bilayer and monolayer models. The lengths of these simulations, the longest single one of which was 2 nanoseconds, were sufficiently long to effectively sample many of the longer-scale motions governing the behaviour of biomembranes. These simulations reproduce many experimental observables well and provide a degree of resolution currently unavailable experimentally.     

汽车碰撞中的人体动力学仿真

将多则体系统动力学中的Ｌ－Ｅ法与经典碰撞理论相结合,推导了树形系统下的Ｌ－Ｅ碰撞动力学方程,并运用面向对象的编程方法开发出汽车碰撞中人体动力学仿真软件,成功地仿真出汽车碰撞后人体运动响应．     

Partitioning of Nonsteroidal Antiinflammatory Drugs in Lipid Membranes: A Molecular Dynamics Simulation Study

Using the potential of mean constrained force method, molecular dynamics simulations with atomistic details were performed to examine the partitioning and nature of interactions of two nonsteroidal antiinflammatory drugs, namely aspirin and ibuprofen, in bilayers of dipalmitoylphosphatidylcholine. Two charge states (neutral and anionic) of the drugs were simulated to understand the effect of protonation or pH on drug partitioning. Both drugs, irrespective of their charge state, were found to have high partition coefficients in the lipid bilayer from water. However, the values and trends of the free energy change and the location of the minima in the bilayer are seen to be influenced by the drug structure and charge state. In the context of the transport of the drugs through the bilayer, the charged forms were found to permeate fully hydrated in contrast to the neutral forms that permeate unhydrated.     

分子动力学模拟与分子生物力学

生物大分子的微观结构动力学决定其生物学功能,其力学-化学耦合规律是分子生物力学的重点关注方向。分子动力学模拟是耦合生物大分子力学-化学性质微观结构动力学基础的有效手段,其结果可用于预测结构-功能关系、指导实验设计和诠释实验结果。本文简要介绍了分子动力学模拟的方法学特点、基本工作原理及其在分子生物力学中的应用,并展望了未来可能的发展方向和应用前景。     

Conformational Flexibility of the Peptide Hormone Ghrelin in Solution and Lipid Membrane Bound: A Molecular Dynamics Study

Abstract

Human ghrelin is a peptide hormone of 28 aminoacid residues, in which the Ser3 is modified by an octanoyl group. Ghrelin has a major role in the energy metabolism of the human body stimulating growth hormone release as well as food intake. Here we perform molecular dynamics simulations in explicit water and in a DMPC-lipid bilayer/water system in order to structurally characterize this highly flexible peptide and its lipid binding properties. We find a loop structure with residues Glu17 to Lys 20 in the bending region and a short α-helix from residues Pro7 to Glu13. The presence of a lipid membrane does not influence these structural features, but reduces the overall flexibility of the molecule as revealed by reduced root mean square fluctuations of the atom coordinates. The octanoyl-side chain does not insert into the lipid membrane but points into the water phase. The peptide binds to the lipid membrane with its bending region involving residues Arg15, Lys16, Glu17, and Ser18. The implications of these results for the binding pocket of the ghrelin receptor are discussed.     

Simulation of Suspensions in Constricted Geometries by Dissipative Particle Dynamics

We investigate the flow of a suspension through a constriction by means of the mesoscopic technique known as dissipative particle dynamics (DPD). The dispersed phase was modeled as a set of soft spheres interacting through a conservative force while suspended and continuum phases interact via DPD forces. It is shown that a Poiseuille steady state is achieved in the presence of bounding walls and under a pressure gradient in a cylindrical pipe. Flow geometry in the laminar regime is explored and discussed for periodic conditions in the presence of a cylindrical narrowing or constriction.     

On the Accuracy Of Some Common Molecular Dynamics Algorithms

Abstract

Attention is drawn to the fact that some of the algorithms used in the simulation of molecular dynamics are less accurate than is commonly believed. In particular, we show that many of the “Verlet-equivalent” integration schemes are not equivalent to the Verlet algorithm, and consequently are not necessarily third order schemes which exhibit exact time-reversal symmetry. Of this class of algorithms, only Beeman's technique is found to generate the optimal positions and velocities for a third order technique. It is also pointed out that the method of constraints introduces errors of O(τ³) into the calculated position, and hence limits the accuracy of simulations that employ this method to second order.     

Molecular Dynamics Simulations for Metallic Nanosystems

Nanotechnology is a crucial field for future scientific development where many different disciplines meet. Computational modelization of nanometer-sized structures is a key issue in this development because (i) it allows a considerable saving of resources and costly experimental setups intended to fabricate nanometric test devices and (ii) nowadays the study of nanometric sized systems is feasible with thoroughly designed computational codes and relatively low cost computational resources. This article describes how molecular dynamics simulations, in combination with potentials obtained in the framework of the embedded atom method, are able to describe the properties of two systems of interest for the development of future nanoelectronic devices: metallic nanowires and metallic nanofilms. Our results show that nanowire stretching results in a series of well-defined geometric structures (shells) and that thin films experiment a crystallographic phase transition for a decreasing number of layers. In both cases, good agreement with experiments is found.     

Lipid mimetics: A versatile toolbox for lipid biology and beyond

Being the principal component of biological membranes lipids are essential building blocks of life. Given their huge biological importance, the investigation of lipids, their properties, interactions and metabolic pathways is of prime importance for the fundamental understanding of living cells and organisms as well as the emergence of diseases. Different strategies have been applied to investigate lipid-mediated biological processes, one of them being the use of lipid mimetics. They structurally resemble their natural counterparts but are equipped with functionality that can be used to probe or manipulate lipid-mediated biological processes and biomembranes. Lipid mimetics therefore constitute an indispensable toolbox for lipid biology and membrane research but also beyond for potential applications in medicine or synthetic biology. Herein, we highlight recent advances in the development and application of lipid-mimicking compounds.     

Interaction of Horse Heart Cytochrome c with Lipid Bilayer Membranes: Effects on Redox Potentials

Cyclic voltammetry has been used to study the effects of interactions between horse cytochrome c and solid-supported planar lipid membranes, comprised of either egg phosphatidylcholine (PC) or PC plus 20 mol.% cardiolipin (CL), on the redox potential and the electrochemical electron transfer rate between the protein and a semiconductor electrode. Experiments were performed over a wide range of cytochrome c concentrations (0–440 M) at low (20 mM) and medium (160 mM) ionic strengths. Three types of electrochemical behavior were observed, which varied as a function of the experimental conditions. At very low cytochrome c concentration (0.1 M), and under conditions where electrostatic forces dominated the protein–lipid membrane interaction (i.e., low ionic strength with membranes containing CL), a redox potential (265 mV) and an electrochemical electron transfer rate constant (0.09s ^–1)were obtained which compare well with those measured in other laboratories using a variety of different chemical modifications of the working electrode. Two other electrochemical signals (not reported with chemically modified electrodes) were also observed to occur at higher cytochrome c concentrations with this membrane system, as well as with two other systems (membranes containing CL under medium ionic strength conditions, and PC only at low ionic strength). These involved positive shifts of the cytochrome c redox potential (by 40 and 60 mV) and large decreases in the electron transfer rate (to 0.03 and 0.003 s^–1). The observations can be rationalized in terms of a structural model of the cytochrome c–membrane interaction, in which association involves both electrostatic and hydrophobic forces and results in varying degrees of insertion of the protein into the hydrophobic interior of the membrane.     

Numerical Calculation of the Bridge Function for Soft-Sphere Supercooled Fluids via Molecular Dynamics Simulations

Abstract

Isokinetic molecular dynamics simulations have been performed for 13,500 soft-spheres interacting through the inverse-power potential, ε([sgrave]/r)ⁿ , near and below the freezing temperature. The bridge function for the integral equation of the theory of liquids is extracted from the pair distribution function (PDF) obtained by the computer simulations for n = 6 and 12. The result is compared with that of approximate theories, i.e., the Rogers-Young (RY) approximation and a modified hypernetted-chain approximation for supercooled soft-sphere fluids (MHNCS approximation). Below the freezing temperature, the bridge function obtained by the computer simulation begins to oscillate around zero at intermediate distances where the second peak of the PDF appears. Such oscillatory behavior of the bridge function is well reproduced by the MHNCS approximation which includes correlations given by the leading elementary diagram, in remarkable contrast to that of the RY approximation. The present result suggests that the split second peak of the PDF for highly supercooled liquids is essentially dominated by the intermediate-distance-range correlation of the leading elementary diagram.