The molecular dynamics of assembly of the ubiquitous aortic medial amyloidal medin fragment

In recent years there is an increased understanding of the molecular conformation of amyloid fibrils. However, much less is known about the early events that lead to the formation of these medically important assemblies. The clarification of these very important mechanistic details on the process may indicate directions towards the inhibition of the early stages of the assembly, where harmful species are most likely to form. Here, we study the dynamics of assembly of short amyloidogenic peptide fragments from the medin polypeptide. This polypeptide is of unique interest since amyloid deposits composed of medin are found almost in all the population above the age of 50. Twelve independent 50 ns long molecular dynamics simulations in explicit water have been run on peptide NH₂–NFGSVQFV–COOH, the minimal recognition hexapeptide element, NH₂–NFGSVQ–COOH, and several single-point mutants. In all cases a three-stranded polymeric β-sheet was used as the basic unit from which fibrils can be formed. Our results clearly indicate the need of well-defined sequence and stereochemical constraints to allow the formation of stable well-ordered aggregates. One of the key findings is the need for the presence of a phenylalanine residue, but not other hydrophobic amino acids, in specific positions within the peptide. Taken together, the results are consistent with recent high-resolution structures of amyloid assemblies and provide unique insights into the dynamics of these structures.     

片斷分子的建立和正則軌道的定域化

为了研究共轭分子的芳香性，我们建立了新的作用能分解法。该方法的核心是为任何一个共轭分子提供一个π和σ体系彻底分离的轨道基组{Φm^P-π，Φt^p-σ，Φf^P}。为此，放射环形环炔烃分子（D3h对称的）必须分割成3个乙炔片断（A，C，E）和3个乙烯片断（B，D，F），经的{Φm^P-π，Φt^p-σ，Φf^P}是由6个片断的轨道基组{ψk^P-π,ψn^P-σ，ψ‘s^P}(P=A,B,…，F）叠加而成。FMP-L和FMP-R（P=A，B，…，F）是片断P的两个片断分子，设它们C-HR键的键长分别是rR(P)和rL(P)。在定域化后，单占据轨道ψ‘s^P和参考氢原子HR占据轨道ψ‘A^H的总电子数∑qs(P) ∑qh(P)总是正确的，与rR(P)和rL(P)的取值无关。但是，{ψ‘s^P}的空间取向取决于rL(P)和rR(P)的值。在片断A和B中，RV（A）=（-V/A）=1.95153 0.50869*rR^V(A),RV(B)=1.94556 0.54823*rR^V(B),设RV=2,则rR^V(A)=0.9528NM,rR^V(B)=0.09930nm。另外，有条件地优化FMP-R可算得：rR^O(A)=0.10658NM,rR^O(B)=0.10888nm。当rR^V(P)和rR^O(P)确定后，可得到；qs^v(A)=6.05124-56.5228*rL^V(A),qs^V(B)=5.17915-47.0804*rL^V(B);qs^O(A)=5.81883-49.0924*rL^O(A),qs^O(B)=4.70043-39.0818*rL^O(B)。然后设qs(P)=qh(P)=(1/4)(∑qs(P) ∑qh(P))，可得到：rL^V(A)=0.08937nm,rL^V(B)=0.08678nm,rL^O(A)=0.09816nm,rL^O(B)=0.09297nm，再由rR^V(P)和rL^V(P)计算的{Φm^P-π，Φt^p-σ，Φf^P}^V中，每一对成键单占据轨道Φt^P的电子占据数Qi比较均匀合理，它的12个单占据轨道的电子总占数为∑Qt=12.3。另外，在由{Φm^P-π，Φt^p-σ，Φf^P}^V算得的FUL态中，轨道分布也是更好地满足FUL态的基本特征。所以rR^V(P)和rL^V(P)比rR^O(P)和rL^O(P)更为合理。     

The MOLDY short-range molecular dynamics package

We describe a parallelised version of the MOLDY molecular dynamics program. This Fortran code is aimed at systems which may be described by short-range potentials and specifically those which may be addressed with the embedded atom method. This includes a wide range of transition metals and alloys. MOLDY provides a range of options in terms of the molecular dynamics ensemble used and the boundary conditions which may be applied. A number of standard potentials are provided, and the modular structure of the code allows new potentials to be added easily. The code is parallelised using OpenMP and can therefore be run on shared memory systems, including modern multicore processors. Particular attention is paid to the updates required in the main force loop, where synchronisation is often required in OpenMP implementations of molecular dynamics. We examine the performance of the parallel code in detail and give some examples of applications to realistic problems, including the dynamic compression of copper and carbon migration in an iron–carbon alloy.

Program summary

Program title: MOLDYCatalogue identifier: AEJU_v1_0Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEJU_v1_0.htmlProgram obtainable from: CPC Program Library, Queen?s University, Belfast, N. IrelandLicensing provisions: GNU General Public License version 2No. of lines in distributed program, including test data, etc.: 382 881No. of bytes in distributed program, including test data, etc.: 6 705 242Distribution format: tar.gzProgramming language: Fortran 95/OpenMPComputer: AnyOperating system: AnyHas the code been vectorised or parallelized?: Yes. OpenMP is required for parallel executionRAM: 100 MB or moreClassification: 7.7Nature of problem: Moldy addresses the problem of many atoms (of order 10⁶) interacting via a classical interatomic potential on a timescale of microseconds. It is designed for problems where statistics must be gathered over a number of equivalent runs, such as measuring thermodynamic properities, diffusion, radiation damage, fracture, twinning deformation, nucleation and growth of phase transitions, sputtering etc. In the vast majority of materials, the interactions are non-pairwise, and the code must be able to deal with many-body forces.Solution method: Molecular dynamics involves integrating Newton?s equations of motion. MOLDY uses verlet (for good energy conservation) or predictor–corrector (for accurate trajectories) algorithms. It is parallelised using open MP. It also includes a static minimisation routine to find the lowest energy structure. Boundary conditions for surfaces, clusters, grain boundaries, thermostat (Nose), barostat (Parrinello–Rahman), and externally applied strain are provided. The initial configuration can be either a repeated unit cell or have all atoms given explictly. Initial velocities are generated internally, but it is also possible to specify the velocity of a particular atom. A wide range of interatomic force models are implemented, including embedded atom, Morse or Lennard-Jones. Thus the program is especially well suited to calculations of metals.Restrictions: The code is designed for short-ranged potentials, and there is no Ewald sum. Thus for long range interactions where all particles interact with all others, the order-N scaling will fail. Different interatomic potential forms require recompilation of the code.Additional comments: There is a set of associated open-source analysis software for postprocessing and visualisation. This includes local crystal structure recognition and identification of topological defects.Running time: A set of test modules for running time are provided. The code scales as order N. The parallelisation shows near-linear scaling with number of processors in a shared memory environment. A typical run of a few tens of nanometers for a few nanoseconds will run on a timescale of days on a multiprocessor desktop.     

Seeding strategies and recombination operators for solving the DNA fragment assembly problem

The fragment assembly problem consists in building the DNA sequence from several hundreds (or even, thousands) of fragments obtained by biologists in the laboratory. This is an important task in any genome project since the rest of the phases depend on the accuracy of the results of this stage. Therefore, accurate and efficient methods for handling this problem are needed. Genetic Algorithms (GAs) have been proposed to solve this problem in the past but a detailed analysis of their components is needed if we aim to create a GA capable of working in industrial applications. In this paper, we take a first step in this direction, and focus on two components of the GA: the initialization of the population and the recombination operator. We propose several alternatives for each one and analyze the behavior of the different variants. Results indicate that using a heuristically generated initial population and the Edge Recombination (ER) operator is the best approach for constructing accurate and efficient GAs to solve this problem.     

分子动力学模拟HEWL晶体在不同环境中的动力学行为

简要阐述分子动力学模拟的原理及步骤,介绍研究溶菌酶的一般方法和优缺点。在Ubuntu操作系统环境下,利用Gromacs软件和其自带的Gromos96力场,通过分子动力学模拟(MD)鸡蛋清溶菌酶晶体(chicken egg-whitelysozyme,HEWL)溶液,考察真空、水溶液和加入NaCl 3种不同环境条件对溶菌酶晶体构象动力学行为的影响,发现无论从均方根位移(rmsd)、回旋半径、还是从B因子值的轨迹图分析,HEWL在水溶液特别是加入抗衡离子(Na~+,Cl~-)的水溶液的环境下的结构更稳定、合理,与(protein data bank)数据库的真实情况相符。原因是Cl~-与溶菌酶晶体在界面处发生了吸附现象,局部形成溶菌酶-Cl~-复合物,抑制了蛋白-水合物中水分子在相邻水合位置间的跳跃,从而使单晶体在离子液态中更加稳定。模拟结果表明,在pH值6.5,等电位点13.1,总电荷7.999 6的体系下,影响HEWL的吸附位点为123号残基(色氨酸),对从分子水平上解释HEWL晶体的动力学吸附行为具有重要指导意义。     

Biophysical applications of molecular dynamics

A survey is given of the computer simulation method of Molecular Dynamics, as applied to complex molecular systems of biological interest. Possibilities and limitations of the method are discussed, with special emphasis on the derivation of free energy from simulations. The prediction of the free energy of binding of an inhibitor to an enzyme is discussed as an example of the application of simulation methods in the field of drug design.     

Stochastic theory of the classical molecular dynamics method

The work is devoted to fundamental aspects of the classical molecular dynamics method, which was developed half a century ago as a means of solving computational problems in statistical physics and has now become one of the most important numerical methods in the theory of condensed state. At the same time, the molecular dynamics method based on solving the equations of motion for a multiparticle system proved to be directly related to the basic concepts of classical statistical physics, in particular, to the problem of the occurrence of irreversibility. This paper analyzes the dynamic and stochastic properties of molecular dynamics systems connected with the local instability of trajectories and the errors of the numerical integration. The probabilistic nature of classical statistics is discussed. We propose a concept explaining the finite dynamic memory time and the emergence of irreversibility in real systems.     

The effect of interatomic potentials on the molecular dynamics simulation of nanometric machining

One of the major tasks in a molecular dynamics (MD) simulation is the selection of adequate potential functions, from which forces are derived. If the potentials do not model the behaviour of the atoms correctly, the results produced from the simulation would be useless. Three popular potentials, namely, Lennard-Jones (LJ), Morse, and embedded-atom method (EAM) potentials, were employed to model copper workpiece and diamond tool in nanometric machining. From the simulation results and further analysis, the EAM potential was found to be the most suitable of the three potentials. This is because it best describes the metallic bonding of the copper atoms; it demonstrated the lowest cutting force variation, and the potential energy is most stable for the EAM.     

深度学习在主动脉中膜变性病理图像分类中的应用

胸主动脉瘤和夹层（TAAD）是严重的心血管疾病之一,而中膜变性（MD）的组织学改变对疾病的诊断及早期干预具有重要的临床意义。针对病理图像的高度复杂性使得MD的诊断过程耗时费力且一致性差的问题,提出了一种基于深度学习的病理图像分类方法,并将其应用于四种MD病变类型以进行性能验证。该方法使用了一种改进的基于GoogLeNet的卷积神经网络模型,首先采用迁移学习来将先验知识应用于TAAD病理图像的表达,然后使用Focal loss和L2正则化来解决数据不平衡问题,从而进一步优化模型性能。实验结果表明,所提模型的平均四分类准确率达到98.78%,表现出较好的泛化性能。可见所提方法可以有效地提升病理学家的诊断效率。     

Ordinary differential equations of molecular dynamics

The ordinary differential equations of Newtonian dynamics are used in atomic simulations with the method of molecular dynamics. The basic issues are surveyed and standard algorithms are described. Several algorithmic variants are discussed. Some advanced ideas relating to parallel computation are considered.     

硅的平衡态分子动力学模拟

平衡态分子动力学模拟是研究既定系统向所期望的平衡态演化的一种方法,不仅可预测平衡态的各种性质,还为动力学加载过程提供合理的初始条件.本文主要研究Free、NVT、NVE平衡态分子动力学模拟中系统宏观量的演化过程;并讨论如何根据不同的初始条件,选择恰当的平衡态模拟方法.     

The human experience [of ubiquitous computing]

To address M. Weiser's (ibid., p. 19-25) human-centered vision of ubiquitous computing, the authors focus on physical interaction, general application features and theories of design and evaluation for this new mode of human-computer interaction.     

黄粉虫α-淀粉酶与抑制剂相互作用的分子动力学模拟

α-淀粉酶与抑制剂相互作用一直受到人们关注。本文利用hyperchem 7.5软件,在opls力场下,选择分子动力学方法,模拟了不同温度条件下,黄粉虫的α-淀粉酶与抑制剂相互作用。通过对势能数据分析,结果显示在280 K左右黄粉虫的α-淀粉酶与抑制剂相互作用最强。这与实验得出的最适温度较为吻合。     

Effect of solvent model when probing protein dynamics with molecular dynamics

We probe the dynamics of the Bpti and Galectin-3 proteins using molecular dynamics simulations employing three water models at different levels of resolution, viz. the atomistic TIP4P-Ewald, the coarse-grained Elba and an implicit generalised Born model. The dynamics are quantified indirectly by model-free order parameters, S² of the backbone NH and selected side-chain bond vectors, which also have been determined experimentally through NMR relaxation measurements. For the backbone, the order parameters produced with the three solvent models agree to a large extent with experiments, giving average unsigned deviations between 0.03 and 0.06. For the side-chains, for which the experimental data is incomplete, the deviations are considerably larger with mean deviations between 0.13 and 0.17. However, for both backbone and side-chains, it is difficult to pick a winner, as all models perform equally well overall. For a more complete set of side-chain vectors, we resort to analysing the variation among the estimates from different solvent models. Unfortunately, the variations are found to be sizeable with mean deviations between 0.11 and 0.15. Implications for computational assessment of protein dynamics are discussed.     

近程作用分子动力学模拟的两级并行

分子动力学作为一种重要的计算手段在许多领域有着广泛的应用,由于它的计算量比较庞大,因此并行计算方法被越来越多地引入到分子动力学的模拟中。本文在目前常见的SMP集群系统上,根据系统的结构特点,针对分子动力学的三种并行算法：区域分解法、原子分解法和力分解法,利用MPI Pthread的混合编程模型,采用节点间消息传递模式以及节点内部共享存储的编程模式,实现了近程作用分子动力学的两级并行计算。计算结果表明,不同的算法采用了两级并行的方式和原来只有消息传递的并行方式相比,具有不同的计算效率,但是从总体来说采用两级并行的计算方式可以利用更多的计算资源,从而有助于提高计算能力。     

双酚A型聚碳酸酯形变行为的MD模拟

采用分子动力学方法(MD),计算了双酚A型聚碳酸酯的应力应/变关系、能量/应变关系.研究中采用了COMPASS力场和NPT系综.应力-应变曲线的研究结果显示,应变εXX≤0.05为"弹性区域",在这一区域,应力-应变有很好的线性关系.在εXX=0.14处出现"屈服点",经过"屈服点",在0.15<εXX<1.0的区域出现应力脉动,应变εXX>1.0后发生了应变硬化.能量-应力关系的研究结果显示,在应力-应变呈线性关系的"弹性区域",体系的总势能及各势能分量随应变增大发生不规则的波动,在"屈服点"附近,Etot与Ebs的变化均产生突跃性的局部高点,而EVW在"屈服点"附近的变化刚好与前两者相反;当体系在经历"屈服区域"时,随着应变的增加,各能量项并不发生明显的变化;当体系处于"应变硬化"阶段时,Etot、Ebs和Ebe会随着应变的增大而继续增大.在整个拉伸过程中,Eto均没有发生明显的变化.对拉伸过程的分子链快照进行分析发现,材料在εXX≤0.16时发生均匀的形变,并维持初始的链结构,同时伴随了一些空穴的生成,在εXX>0.6时,可以清楚地看到密度变得不均匀.在εXX>1.0的应变硬化的初始阶段,新的网络结构生成了,长的直链与缠绕链形成的团簇相连.