Comparative structural studies of psychrophilic and mesophilic protein homologues by molecular dynamics simulation

Comparative molecular dynamics simulations of psychrophilic type III antifreeze protein from the North-Atlantic ocean-pout Macrozoarces americanus and its corresponding mesophilic counterpart, the antifreeze-like domain of human sialic acid synthase, have been performed for 10 ns each at five different temperatures. Analyses of trajectories in terms of secondary structure content, solvent accessibility, intramolecular hydrogen bonds and protein–solvent interactions indicate distinct differences in these two proteins. The two proteins also follow dissimilar unfolding pathways. The overall flexibility calculated by the trace of the diagonalized covariance matrix displays similar flexibility of both the proteins near their growth temperatures. However at higher temperatures psychrophilic protein shows increased overall flexibility than its mesophilic counterpart. Principal component analysis also indicates that the essential subspaces explored by the simulations of two proteins at different temperatures are non-overlapping and they show significantly different directions of motion. However, there are significant overlaps within the trajectories and similar directions of motion of each protein especially at 298 K, 310 K and 373 K. Overall, the psychrophilic protein leads to increased conformational sampling of the phase space than its mesophilic counterpart.Our study may help in elucidating the molecular basis of thermostability of homologous proteins from two organisms living at different temperature conditions. Such an understanding is required for designing efficient proteins with characteristics for a particular application at desired working temperatures.     

Comparative unfolding studies of psychrophilic and mesophilic uracil DNA glycosylase: MD simulations show reduced thermal stability of the cold-adapted enzyme

Uracil DNA glycosylase (UDG) is a DNA repair enzyme involved in the base excision repair (BER) pathway, removing misincorporated uracil from the DNA strand. The native and mutant forms of Atlantic cod and human UDG have previously been characterized in terms of kinetic and thermodynamic properties as well as the determination of several crystal structures. This data shows that the cold-adapted enzyme is more catalytically efficient but at the same time less resistant to heat compared to its warm-active counterpart. In this study, the structure-function relationship is further explored by means of comparative molecular dynamics (MD) simulations at three different temperatures (375, 400 and 425K) to gain a deeper insight into the structural features responsible for the reduced thermostability of the cold-active enzyme. The simulations show that there are distinct structural differences in the unfolding pathway between the two homologues, particularly evident in the N- and C-terminals. Distortion of the mesophilic enzyme is initiated simultaneously in the N- and C-terminal, while the C-terminal part plays a key role for the stability of the psychrophilic enzyme. The simulations also show that at certain temperatures the cold-adapted enzyme unfolds faster than the warm-active homologues in accordance with the lower thermal stability found experimentally.     

Membrane protein structure quality in molecular dynamics simulation

Our goal was to assess the relationship between membrane protein quality, output from protein quality checkers and output from molecular dynamics (MD) simulations. Membrane transport proteins are essential for a wide range of cellular processes. Structural features of integral membrane proteins are still under-explored due to experimental limitations in structure determination. Computational techniques can be used to exploit biochemical and medium resolution structural data, as well as sequence homology to known structures, and enable us to explore the structure-function relationships in several transmembrane proteins. The quality of the models produced is vitally important to obtain reliable predictions. An examination of the relationship between model stability in molecular dynamics (MD) simulations derived from RMSD (root mean squared deviation) and structure quality assessment from various protein quality checkers was undertaken. The results were compared to membrane protein structures, solved at various resolution, by either X-ray or electron diffraction techniques. The checking programs could predict the potential success of MD in making functional conclusions. MD stability was shown to be a good indicator for the quality of structures. The quality was also shown to be dependent on the resolution at which the structures were determined.     

分子动力学模拟的柔性对接

分子自动对接技术在过去二十年里取得很大发展和成功,但是仍然面对如何处理分子柔性这样一个难题。这篇综述概要介绍分子柔性对接技术的进展并重点介绍分子动力学模拟技术。     

Algorithm optimization in molecular dynamics simulation

Establishing the neighbor list to efficiently calculate the inter-atomic forces consumes the majority of computation time in molecular dynamics (MD) simulation. Several algorithms have been proposed to improve the computation efficiency for short-range interaction in recent years, although an optimized numerical algorithm has not been provided. Based on a rigorous definition of Verlet radius with respect to temperature and list-updating interval in MD simulation, this paper has successfully developed an estimation formula of the computation time for each MD algorithm calculation so as to find an optimized performance for each algorithm. With the formula proposed here, the best algorithm can be chosen based on different total number of atoms, system average density and system average temperature for the MD simulation. It has been shown that the Verlet Cell-linked List (VCL) algorithm is better than other algorithms for a system with a large number of atoms. Furthermore, a generalized VCL algorithm optimized with a list-updating interval and cell-dividing number is analyzed and has been verified to reduce the computation time by 30∼60% in a MD simulation for a two-dimensional lattice system. Due to similarity, the analysis in this study can be extended to other many-particle systems.     

分子动力学并行算法的优化与应用

比较了小型机群中模拟小规模粒子系统采用原子分解和区域分解算法的模拟时间.针对原子分解算法,优化了各进程粒子的受力计算,尤其对严重影响并行效率的全局通信进行了优化,最终使得并行效率提高了30%以上.使用该优化算法对固态氩的导热系数进行了计算,模拟结果与实验值比较吻合,大大缩短了时间.     

Structural insights into the camel milk lactoperoxidase: Homology modeling and molecular dynamics simulation studies

Lactoperoxodase (LPO) is a heme peroxidase enzyme present in mammalian milk. It is an antimicrobial protein with wide range of industrial applications. Although the three dimensional structure of LPO from various mammalian species has been reported, but its structure from camel source is still unknown. So far, the crystallization attempts have not been successful in determining camel LPO (cLPO) structure. Herein, we developed the three dimensional structure of cLPO by homology modeling approach using prime module available in Schrodinger suite. The developed model in complex with ligand hypothiocyanate (OSCN⁻) was further validated by Ramachandran plot followed by molecular dynamics (MD) simulation studies using Desmond module of Schrodinger. cLPO model exhibited overall structural similarity with template crystal structure, however, it displayed different interaction pattern of amino acid residues with ligand OSCN⁻ in comparison to template crystal structure. Moreover, the ligand binding site environment in cLPO is more polar, less hydrophobic, and harbours more number of charged residues than template crystal structure. The substrate binding pocket environment of cLPO shows a considerable difference from template crystal structure. This subsequently resulted in dissimilar behaviour of ligand during the course of MD simulation studies.     

Huge-scale molecular dynamics simulation of multibubble nuclei

We have developed molecular dynamics codes for a short-range interaction potential that adopt both the flat-MPI and MPI/OpenMP hybrid parallelizations on the basis of a full domain decomposition strategy. Benchmark simulations involving up to 38.4 billion Lennard-Jones particles were performed on Fujitsu PRIMEHPC FX10, consisting of 4800 SPARC64 IXfx 1.848 GHz processors, at the Information Technology Center of the University of Tokyo, and a performance of 193 teraflops was achieved, which corresponds to a 17.0% execution efficiency. Cavitation processes were also simulated on PRIMEHPC FX10 and SGI Altix ICE 8400EX at the Institute of Solid State Physics of the University of Tokyo, which involved 1.45 billion and 22.9 million particles, respectively. Ostwald-like ripening was observed after the multibubble nuclei. Our results demonstrate that direct simulations of multiscale phenomena involving phase transitions from the atomic scale are possible and that the molecular dynamics method is a promising method that can be applied to petascale computers.     

Insights into thermal stability of thermophilic nitrile hydratases by molecular dynamics simulation

Thermal stability is of great importance for industrial enzymes. Here we explored the thermal-stable mechanism of thermophilic nitrile hydratases (NHases) utilizing a molecular dynamic simulation. At a nanosecond timescale, profiles of root mean square fluctuation (RMSF) of two thermophilic NHases, 1UGQ and 1V29, under enhancing thermal stress were carried out at 300 K, 320 K, 350 K and 370 K, respectively. Results showed that the region A1 (211-231 aa) and A2 (305-316 aa) in 1UGQ, region B1 (186-192 aa) in 1V29, and most of terminal ends in both enzymes are hyper-sensitive. Salt-bridge analyses revealed that in one hand, salt-bridges contributed to maintaining the rigid structure and stable performance of the thermophilic 1UGQ and 1V29; in the other hand, salt-bridges involved in thermal sensitive regions are relatively weak and prone to be broken at elevated temperature, thereby cannot hold the stable conformation of the spatial neighborhood. In 1V29, region A1 was stabilized by a well-organized hook-hook like cluster with multiple salt-bridge interactions, region A2 was stabilized by two strong salt-bridge interactions of GLU52-ARG332 and GLU334-ARG332. In 1UGQ, the absence of a charged residue decreased its thermal sensitivity of region B1, and the formation of a small beta-sheet containing a stable salt-bridge in C-beta-terminal significantly enhanced its thermal stability. By radius of gyration calculation containing or eliminating the thermal sensitive regions, we quantified the contribution of thermal sensitive regions for thermal sensitivity of 1UGQ and 1V29. Consequently, we presented strategies to improve thermal stability of the industrialized mesophilic NHase by introducing stable salt-bridge interactions into its thermal sensitive regions.     

Temperature-induced unfolding pathway of a type III antifreeze protein: insight from molecular dynamics simulation

Molecular dynamics simulations of the temperature-induced unfolding reaction of a cold-adapted type III antifreeze protein (AFPIII) from the Antarctic eelpout Lycodichthys dearborni have been carried out for 10 ns each at five different temperatures. While the overall character and order of events in the unfolding process are well conserved across temperatures, there are substantial differences in the timescales over which these events take place. Plots of backbone root mean square deviation (RMSD) against radius of gyration (Rg) serve as phase space trajectories. These plots also indicate that the protein unfolds without many detectable intermediates suggestive of two-state unfolding kinetics. The transition state structures are identified from essential dynamics, which utilizes a principal component analysis (PCA) on the atomic fluctuations throughout the simulation. Overall, the transition state resembles an expanded native state with the loss of the three 3₁₀ helices and disrupted C-terminal region.Our study provides insight into the structure–stability relationship of AFPIII, which may help to engineer AFPs with increased thermal stability that is more desirable than natural AFPs for some industrial and biomedical purposes.     

分子动力学模拟蛋白质溶液吸附过程构象的变化

计算机模拟作为一种工具在药物分子设计、蛋白质工程、药物筛选等方面逐渐广泛应用起来。为了从分子水平上理解蛋白质吸附的机理，本文采用了刚体模型对聚十赖氨酸在固体表面吸附进行了分子动力学模拟。采用立方周期性边界条件，模拟在NVT条件下进行，各刚体的起始速度按Maxwell取样。初步研究了模拟过程中蛋白质构象的变化，跟踪了吸附过程中二面角φ和ψ的变化。研究结果表明，吸附过程中蛋白质二级结构发生了变化，C末端二级结构的变化最为明显。     

多核CPU和GPU加速分子动力学模拟

在多核中央处理器(CPU)—图形处理器(GPU)异构并行体系结构上,采用OpenMP和计算统一设备架构(CUDA)编程实现了基于AMBER力场的蛋白质分子动力学模拟程序。通过合理地将程序划分为CPU单线程、CPU多线程和GPU多线程执行部分,高效地利用了计算机的处理能力。性能测试结果表明,相对于优化后的CPU串行计算,多核CPU-GPU异构并行计算模型有强大的性能优势,特别是将占整个程序执行时间90%的作用力的计算移植到GPU上执行,获得了最高可达12倍的计算加速比。     

短程力分子模拟在Hadoop上的实现及优化

在Hadoop开源云计算平台上运行分子模拟程序,具有节省软硬件投资、缩短模拟时间等研究意义。然而,该平台并不擅长科学计算类应用中所涉及的快速迭代和子任务间通信。为此,在原子分解法基础上提出了三种解决方案并利用"读写HDFS同步法"实现短程作用力有效的分子动力学模拟的并行算法。在一个Hadoop集群上测试和分析了程序的可扩展性、加速比和各部分耗时情况,结果表明在大规模体系模拟中有较好的效果,最高取得了28倍的加速比。实验证明,Hadoop并行技术在分子模拟中有着较高的经济价值和实用价值。     

Equilibrium molecular dynamics studies on nanoscale-confined fluids

Fluid behavior within nanoscale confinements is studied for argon in dilute gas, dense gas, and liquid states. Molecular dynamics simulations are used to resolve the density and stress variations within the static fluid. Normal stress calculations are based on the Irving–Kirkwood method, which divides the stress tensor into its kinetic and virial parts. The kinetic component recovers pressure based on the ideal-gas law. The particle–particle virial increases with increased density, whereas the surface–particle virial develops because of the surface-force field effects. Normal stresses within nanoscale confinements show anisotropy primarily induced by the surface-force field and local variations in the fluid density near the surfaces. For dilute and dense gas cases, surface-force field that extends typically 1 nm from each wall induces anisotropic normal stress. For liquid case, this effect is further amplified by the density fluctuations that extend beyond the force field penetration region. Outside the wall-force field penetration and density fluctuation regions, the normal stress becomes isotropic and recovers the thermodynamic pressure, provided that sufficiently large force cut-off distances are used in the computations.     

A general purpose parallel molecular dynamics simulation program

We present a general purpose parallel molecular dynamics simulation code. The code can handle NVE, NVT, and NPT ensemble molecular dynamics, Langevin dynamics, and dissipative particle dynamics. Long-range interactions are handled by using the smooth particle mesh Ewald method. The implicit solvent model using solvent-accessible surface area was also implemented. Benchmark results using molecular dynamics, Langevin dynamics, and dissipative particle dynamics are given.

Program summary

Title of program:MM_PARCatalogue identifier:ADXP_v1_0Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADXP_v1_0Program obtainable from: CPC Program Library, Queen's University of Belfast, N. IrelandComputer for which the program is designed and others on which it has been tested:any UNIX machine. The code has been tested on Linux cluster and IBM p690Operating systems or monitors under which the program has been tested:Linux, AIXProgramming language used:CMemory required to execute with typical data:∼60 MB for a system of atoms Has the code been vectorized or parallelized? parallelized with MPI using atom decomposition and domain decompositionNo. of lines in distributed program, including test data, etc.:171 427No. of bytes in distributed program, including test data, etc.:4 558 773Distribution format:tar.gzExternal routines/libraries used:FFTW free software (http://www.fftw.org)Nature of physical problem:Structural, thermodynamic, and dynamical properties of fluids and solids from microscopic scales to mesoscopic scales.Method of solution:Molecular dynamics simulation in NVE, NVT, and NPT ensemble, Langevin dynamics simulation, dissipative particle dynamics simulation.Typical running time:Table below shows the typical run times for the four test programs.

Benchmark results. The values in the parenthesis are the number of processors used
System	Method	Timing for 100 steps in seconds
256 TIP3P	MD	23.8 (1)
64 DMPC + 1645 TIP3P	MD	890 (1)	528 (2)	326 (4)	209 (8)
8 Aβ16-22	LD	1.02 (1)
23760 Groot-Warren particles	DPD	22.16 (1)

Full-size table

     

Crystal morphology prediction of 1,3,3-trinitroazetidine in ethanol solvent by molecular dynamics simulation

In order to understand the mechanism of the effect of solvent on the crystal morphology of explosives, and be convenient for the choice of crystallization solvent, the attachment energy (AE) model was performed to predict the growth morphology and the main crystal faces of 1,3,3-trinitroazetidine (TNAZ) in vacuum. The molecular dynamics simulation was applied to investigate the interactions of TNAZ crystal faces and ethanol solvent, and the growth habit of TNAZ in ethanol solvent was predicted using the modified AE model. The results indicate that the morphology of TNAZ crystal in vacuum is dominated by the six faces of [0 2 1], [1 1 2], [0 0 2], [1 0 2], [1 1 1] and [0 2 0], and the crystal shape is similar to polyhedron. In ethanol solvent, The binding strength of ethanol with TNAZ faces changes in the order of [0 2 1] > [1 1 2] > [0 0 2] > [1 0 2] > [1 1 1] > [0 2 0], which causes that [1 1 1] and [0 2 0] faces disappear and the crystal morphology becomes more regular. The radial distribution function analysis shows that the interactions between solvent and crystal faces mainly consist of coulomb interaction, van der Waals force and hydrogen bonds.     

丁二酰亚胺类分散剂在伪烟炱表面吸附行为的分子动力学模拟

丁二酰亚胺类分散剂是一种典型的用于各种润滑油中的无灰分散剂。由于烟炱颗粒结构的复杂性,从实验研究的角度对分散剂的作用机理尚未给出满意的解释。本文应用分子动力学模拟方法,研究了丁二酰亚胺类分散剂模型分子在伪烟炱表面的吸附行为。模拟结果可以为分散剂的分子设计提供参考。     

Structural study of carboxylesterase from hyperthermophilic bacteria Geobacillus stearothermophilus by molecular dynamics simulation

Carboxylesterases are ubiquitous enzymes with important physiological, industrial and medical applications such as synthesis and hydrolysis of stereo specific compounds, including the metabolic processing of drugs, and antimicrobial agents. Here, we have performed molecular dynamics simulations of carboxylesterase from hyperthermophilic bacterium Geobacillus stearothermophilus (GsEst) for 10 ns each at five different temperatures namely at 300 K, 343 K, 373 K, 473 K and 500 K. Profiles of root mean square fluctuation (RMSF) identify thermostable and thermosensitive regions of GsEst. Unfolding of GsEst initiates at the thermosensitive α-helices and proceeds to the thermostable β-sheets. Five ion-pairs have been identified as critical ion-pairs for thermostability and are maintained stably throughout the higher temperature simulations. A detailed investigation of the active site residues of this enzyme suggests that the geometry of this site is well preserved up to 373 K. Furthermore, the hydrogen bonds between Asp188 and His218 of the active site are stably maintained at higher temperatures imparting stability of this site. Radial distribution functions (RDFs) show similar pattern of solvent ordering and water penetration around active site residues up to 373 K. Principal component analysis suggests that the motion of the entire protein as well as the active site is similar at 300 K, 343 K and 373 K. Our study may help to identify the factors responsible for thermostability of GsEst that may endeavor to design enzymes with enhanced thermostability.     

多核并行技术在分子动力学模拟中的应用

为了充分利用多核处理器资源,研究了一种用于分子动力学模拟中的多核并行技术。在多核处理器上利用OpenMP技术实现多线程创建与同步、动态设置子线程的调度运行方式以及负载均衡以减少子线程执行等待时间。通过对不同分子体系结构下的动力学模型测试,得出在不同子线程下并行计算的时间,并且得到了良好的性能加速比。实验结果表明,采用OpenMP并行技术可有效地提高电荷求解过程在分子动力学模拟运算中的时间效率,以及多核计算机资源的利用率。