基于接触数引导的迭代多组独立分子动力学模拟实现配体-蛋白质结合与解离过程（英文）

配体的结合与解离过程在蛋白质实现其生物学功能方面非常关键,因此对这些高度动态过程的研究变得非常重要.尽管已有实验方法可以确定蛋白质-配体复合物的三维结构,但一般仅可获得静态图片.随着计算机算力的快速提高以及算法的优化,分子动力学模拟在探索配体的结合与解离过程方面具有诸多优势.然而,当系统变得足够大时,分子动力学模拟的时间和空间尺度成为了巨大的挑战.本工作提出了一种研究配体-蛋白质结合与解离的增强采样工具,它基于配体和蛋白质之间形成的接触数来引导迭代多组独立分子动力学模拟.在腺苷酸激酶的模拟结果中,观测到配体的结合和解离过程,而使用传统分子动力学模拟在同一时间尺度下则无法实现这一过程.     

钨空位捕获氢及其解离过程的分子动力学

氢(H)同位素滞留问题是聚变堆第一壁材料设计的关键,而深入理解H在缺陷(如空位)处的非均匀形核长大过程有助于揭示H起泡及滞留的机制.针对第一壁材料钨(W)中空位捕获H及其解离的动力学过程开展研究,通过耦合捕获和解离两过程,构建新物理模型,避免了原单一过程的物理模型需准确记录相应事件首次发生时间的不足,另外新模型可同时提取解离系数和有效捕获半径等动力学参数.通过分子动力学模拟发现新模型能较好地描述W中空位-H复合体对H捕获和解离的动力学过程,根据空位-H复合体随时间的演化曲线,提取了有效捕获半径和解离系数等动力学参数.一方面能为动力学蒙特卡罗和速率理论等长时空尺度方法提供输入参数,另一方面促进了分子动力学的发展,进而实现了以较低计算资源获得更可靠的计算结果.     

纳米孔壁面作用对蛋白质过孔影响的粗粒化分子动力学模拟

基于粗粒化分子动力学方法模拟电驱动蛋白质过孔过程，研究纳米孔-水/纳米孔-蛋白质相互作用对电泳迁移率的影响；用操控式分子动力学模拟分析蛋白质在不同相互作用下过孔摩擦系数和摩擦阻力.研究发现：蛋白质黏附纳米孔壁面对其过孔特性影响并不明显，而纳米孔-水相互作用对蛋白质过孔电泳迁移率和摩擦系数影响较大.随纳米孔-水相互作用增强，纳米孔壁面与蛋白质附近水分子运动差异显现，蛋白质过孔摩擦阻力显著增大，过孔摩擦系数随之增大，进而影响蛋白质过孔电泳迁移率.所得结果可为纳米孔材料设计提供理论指导.     

元胞方法与蒙特卡洛方法相结合的薄膜生长过程模拟

利用仿真方法从原子尺度研究薄膜生长过程是当前薄膜研究领域的热点. 目前, 仿真方法主要在纳米尺度模型实现, 时空需求很大. 针对这一问题, 本文提出元胞和蒙特卡洛相结合的模拟方法, 实现对微米尺度模型薄膜生长过程的模拟. 利用元胞方法来实现模型表示以及演化计算, 从而降低对内存空间的要求, 提高计算效率, 并使用蒙特卡洛方法计算粒子的扩散概率. 通过对氮化硅薄膜生长过程进行具体研究, 将模拟结果与实际实验结果和分子动力学演化结果进行表面形貌和成分的比较, 验证了该方法的有效性.     

二聚物在Cu表面上的扩散和解离研究

利用分子动力学模拟统计了几种不同温度下三种不同二聚物(Cu₂, Ag₂和Pd₂)在铜衬底(100), (111)表面上的扩散和解离行为, 探讨同质和异质二聚物在Cu表面上扩散和解离的特点; 采用分子动力学中的静态计算方法计算了这三种二聚物在扩散和解离过程中的能量势垒, 并与动力学模拟、二聚物与衬底的结合能等结果进行了比较, 探讨二聚物扩散和解离过程与扩散势垒、结合能、表面性质和温度等的关系. 原子间相互作用采用半经验EAM势. 结果表明: 同质和异质二聚物在各个不同表面上的扩散势垒、解离势垒有一定的规律, 并和二聚物与衬底的结合性质有关; 二聚物是否易解离与衬底表面的结构以及二聚物与衬底的结合性质关系密切; 二聚物解离前协同扩散的快慢与二聚物和衬底的结合性质以及二聚物在表面的扩散和解离势垒密切相关.     

固态高分子体系多尺度分子运动的核磁共振研究

固体核磁共振技术是研究固态高分子材料中结构和分子动力学的一种非常重要和有效的手段. 该技术的一个重要特点是可以通过合理的实验方法,实现对研究体系中从低频(Hz)到中频(kHz)乃至高频(MHz)范围内分子运动的观测. 因此,固体核磁共振技术非常适合研究高分子体系中各类不同尺度分子运动. 该文首先简要介绍核磁共振研究分子运动的基本原理和方法,以及固态高分子体系的结构和分子动力学特点,然后结合固态高分子体系中的一些例子对核磁共振在固态高分子多尺度分子运动方面的一些研究成果展开讨论.     

用NMR技术研究蛋白质-配体相互作用

蛋白质-配体相互作用的研究对理解生命过程、药物设计和药物筛选具有相当重要的科学意义和巨大的经济价值. NMR是研究蛋白质-配体相互作用的最有用的技术之一,有着显著的优势. 本文综述了近年来国际上用NMR技术研究蛋白质-配体相互作用的发展状况和趋势,先介绍表征蛋白质-配体相互作用的重要参数,然后介绍如何判断蛋白质或配体与复合物的化学交换类型以及所能获得的有关蛋白质-配体相互作用的信息,最后介绍具体用于研究蛋白质-配体相互作用的若干NMR技术以及基于NMR的药物筛选技术.     

基于TorchMD的粗粒化分子动力模拟研究

粗粒化模型通过简化原子性质以及原子间的相互作用实现生物大分子长时间尺度的分子动力学模拟. 深度学习通过模拟人类的认知过程实现海量数据的准确分类和回归过程. 本论文将这两种技术进行融合,利用基于深度学习的粗粒化分子动力学模拟技术研究分子在不同状态之间的变化过程,并提出基于TorchMD的分子动力学模拟的分析框架. 在本工作中,MFDP聚类算法被用于在三维的CV变量空间中进行聚类,并确定分子的若干主要状态,在完成聚类的同时,给出各类中的代表分子构象,并给出类之间的分子构象. 这为后续利用String算法分析分子在不同状态间的转换路径打下基础. 通过String算法,迭代搜索得到分子在不同状态之间的变化路径以及对应的势能变化曲线. 通过与已有文献的结果进行对比,验证了基于TorchMD的粗粒化分子动力学模拟的理论框架可以在相对较短的时间尺度里研究分子的变化过程.     

基于荧光数据计算蛋白质-配体结合常数的方程的对比及应用研究

蛋白质和配体的结合作用在生物体的生理生化过程中具有重要作用,是诸多领域的研究热点。研究蛋白质-配体结合作用的一个关键目标,就是获得两者的结合常数(K_b)以评价其结合作用的强弱。荧光光谱法具有灵敏度高、方便快速及成本低的优点,被广泛用于蛋白质-配体结合作用的研究中。应用荧光光谱法时,借助函数方程对荧光数据进行数学分析来得到K_b值是一个关键步骤。因不同方程的适用范围不同,应用于同一体系所获得的K_b值往往存在差异。针对此问题,一方面讨论了利用荧光光谱数据计算蛋白质和配体结合的K_b值的函数方程的推导过程及其适用条件,总结出不同前提条件下蛋白质-配体1∶1和1∶n(n≥2)结合时可选择的计算K_b值的最优方程。分析表明,选择最优方程应基于两个前提:a:蛋白质与配体结合后形成的复合物是否产生荧光; b:添加的配体浓度是否远大于蛋白质浓度。另一方面,以人血清白蛋白(HSA)-诺氟沙星(NFX)结合体系作为模型,对比了由不同方程拟合得到的K_b值的差异并探讨了相应原因。结果表明, HSA与NFX为1∶1结合,利用最适用该体系的方程(S12)拟合得到其在298 K下的K_b值为5.0×10~4 L·mol~(-1),而使用方程(S6)和方程(S24)拟合得到的K_b值分别比该值大28.8%和48.6%,由方程(S17)得到的值则比该值约高2个数量级。这直观地展示了选择不适用的方程对所获结果的影响。此外,将利用荧光光谱法获得的K_b值与其他方法获得的数据做了对比,说明了利用荧光光谱法计算蛋白质-配体K_b值的相对可靠性,同时也指出了该方法的局限性。结果表明,在利用荧光光谱数据获得蛋白质-配体结合的K_b值时,依据前提条件(即假设a和/或b是否成立)来选取最适合的函数方程是非常必要的,其将决定所得结果的可靠性。     

冲击作用下纳米孔洞动力学行为的多尺度方法模拟研究

本文利用多尺度方法研究了包含孔洞金属材料在冲击加载条件下的动力学行为. 该多尺度方法结合了分子动力学和有限元方法,分子动力学方法运用于局部缺陷区域,而有限元方法运用于整个模型区域,两种方法之间使用桥尺度函数进行连接. 计算结果既包括了系统宏观的物理信息,如应变场、应力场、温度场等,也得到了微观原子的物理信息,如原子能量和位置坐标等. 结合以上的模拟结果,发现孔洞的坍塌与材料屈服强度和冲击强度有关,而孔洞坍塌和坍塌过程中对微喷射原子的压缩过程是形成局部热点的主要原因. 同时也发现孔洞坍塌形成的位错和局部热点可以导致局部绝热剪切带更容易形成. 关键词： 微孔洞 热点 冲击加载 多尺度方法     

A network of conformational transitions in an unfolding process of HP-35 revealed by high-temperature MD simulation and a Markov state model

An understanding of protein folding/unfolding processes has important implications for all biological processes, including protein degradation, protein translocation, aging, and diseases. All-atom molecular dynamics(MD) simulations are uniquely suitable for it because of their atomic level resolution and accuracy. However, limited by computational capabilities, nowadays even for small and fast-folding proteins, all-atom MD simulations of protein folding still presents a great challenge. An alternative way is to study unfolding process using MD simulations at high temperature. High temperature provides more energy to overcome energetic barriers to unfolding, and information obtained from studying unfolding can shed light on the mechanism of folding. In the present study, a 1000-ns MD simulation at high temperature(500 K)was performed to investigate the unfolding process of a small protein, chicken villin headpiece(HP-35). To infer the folding mechanism, a Markov state model was also built from our simulation, which maps out six macrostates during the folding/unfolding process as well as critical transitions between them, revealing the folding mechanism unambiguously.     

Quasi-coarse-grained dynamics: modelling of metallic materials at mesoscales

A computationally efficient modelling method called quasi-coarse-grained dynamics (QCGD) is developed to expand the capabilities of molecular dynamics (MD) simulations to model behaviour of metallic materials at the mesoscales. This mesoscale method is based on solving the equations of motion for a chosen set of representative atoms from an atomistic microstructure and using scaling relationships for the atomic-scale interatomic potentials in MD simulations to define the interactions between representative atoms. The scaling relationships retain the atomic-scale degrees of freedom and therefore energetics of the representative atoms as would be predicted in MD simulations. The total energetics of the system is retained by scaling the energetics and the atomic-scale degrees of freedom of these representative atoms to account for the missing atoms in the microstructure. This scaling of the energetics renders improved time steps for the QCGD simulations. The success of the QCGD method is demonstrated by the prediction of the structural energetics, high-temperature thermodynamics, deformation behaviour of interfaces, phase transformation behaviour, plastic deformation behaviour, heat generation during plastic deformation, as well as the wave propagation behaviour, as would be predicted using MD simulations for a reduced number of representative atoms. The reduced number of atoms and the improved time steps enables the modelling of metallic materials at the mesoscale in extreme environments.     

Effect of interaction between loop bases and ions on stability of G-quadruplex DNA

G-quadruplexes(GQs) are guanine-rich, non-canonical nucleic acid structures that play fundamental roles in biological processes. The topology of GQs is associated with the sequences and lengths of DNA, the types of linking loops, and the associated metal cations. However, our understanding on the basic physical properties of the formation process and the stability of GQs is rather limited. In this work, we employed ab initio, molecular dynamics(MD), and steered MD(SMD)simulations to study the interaction between loop bases and ions, and the effect on the stability of G-quadruplex DNA, the Drude oscillator model was used in MD and SMD simulations as a computationally efficient manner method for modeling electronic polarization in DNA ion solutions. We observed that the binding energy between DNA bases and ions(K⁺/Na⁺)is about the base stacking free energies indicates that there will be a competition among the binding of M⁺-base, H-bonds between bases, and the base-stacking while ions were bound in loop of GQs. Our SMD simulations indicated that the side loop inclined to form the base stacking while the loop sequence was Thy or Ade, and the cross-link loop upon the G-tetrads was not easy to form the base stacking. The base stacking side loop complex K+was found to have a good stabilization synergy. Although a stronger interaction was observed to exist between Cyt and K+, such an interaction was unable to promote the stability of the loop with the sequence Cyt.     

A Simple Model-Free Method for Direct Assessment of Fluorescent Ligand Binding by Linear Spectral Summation

Fluorescent tagged ligands are commonly used to determine binding to proteins. However, bound and free ligand concentrations are not directly determined. Instead the response in a fluorescent ligand titration experiment is considered to be proportional to the extent of binding and, therefore, the maximum value of binding is scaled to the total protein concentration. Here, a simple model-free method is presented to be performed in two steps. In the first step, normalized bound and free spectra of the ligand are determined. In the second step, these spectra are used to fit composite spectra as the sum of individual components or linear spectral summation. Using linear spectral summation, free and bound 1-Anilinonaphthalene-8-Sulfonic Acid (ANS) fluorescent ligand concentrations are directly calculated to determine ANS binding to tear lipocalin (TL), an archetypical ligand binding protein. Error analysis shows that the parameters that determine bound and free ligand concentrations were recovered with high certainty. The linear spectral summation method is feasible when fluorescence intensity is accompanied by a spectral shift upon protein binding. Computer simulations of the experiments of ANS binding to TL indicate that the method is feasible when the fluorescence spectral shift between bound and free forms of the ligand is just 8 nm. Ligands tagged with environmentally sensitive fluorescent dyes, e.g., dansyl chromophore, are particularly suitable for this method.

平衡和非平衡方法计算相对结合自由能的精度和效率比较

Estimation of protein-ligand binding affinity within chemical accuracy is one of the grand challenges in structure-based rational drug design. With the efforts over three decades, free energy methods based on equilibrium molecular dynamics (MD) simulations have become mature and are nowadays routinely applied in the community of computational chemistry. On the contrary, nonequilibrium MD simulation methods have attracted less attention, despite their underlying rigor in mathematics and potential advantage in efficiency. In this work, the equilibrium and nonequilibrium simulation methods are compared in terms of accuracy and convergence rate in the calculations of relative binding free energies. The proteins studied are T4-lysozyme mutant L99A and COX-2. For each protein, two ligands are studied. The results show that the nonequilibrium simulation method can be competitively as accurate as the equilibrium method, and the former is more efficient than the latter by considering the convergence rate with respect to the cost of wall clock time. In addition, Bennett acceptance ratio, which is a bidirectional post-processing method, converges faster than the unidirectional Jarzynski equality for the nonequilibrium simulations.     

Simulation of screw dislocation motion in iron by molecular dynamics simulations

Molecular dynamics (MD) simulations are used to investigate the response of a/2<111> screw dislocation in iron submitted to pure shear strain. The dislocation glides and remains in a (110) plane; the motion occurs exclusively through the nucleation and propagation of double kinks. The critical stress is calculated as a function of the temperature. A new method is developed and used to determine the activation energy of the double kink mechanism from MD simulations. It is shown that the differences between experimental and simulation conditions lead to a significant difference in activation energy. These differences are explained, and the method developed provides the link between MD and mesoscopic simulations.     

Peculiar diffusion behavior of AlCl_4 intercalated in graphite from nanosecond-long molecular dynamics simulations

The diffusion property of the intercalated species in the graphite materials is at the heart of the rate performance of graphite-based metal-ion secondary battery. Here we study the diffusion process of a AlCl_4 molecule within graphite — a key component of a recently reported aluminum ion battery with excellent performance — via molecular dynamics(MD) simulations. Both ab-initio MD(AIMD) and semiempirical tight-binding MD simulations show that the diffusion process of the intercalated AlCl_4 molecule becomes rather inhomogeneous, when the simulation time exceeds approximately 100 picoseconds. Specifically, during its migration in between graphene layers, the intercalated AlCl_4 molecule may become stagnant occasionally, and then recovers its normal(fast) diffusion behavior after halting for a while. When this phenomenon occurs, the linear relationship of the mean squared displacement(MSD) versus the duration time is not fulfilled. We interpret this peculiar behavior as a manifestation of inadequate sampling of rare event(the stagnation of the molecule), which does not yet appear in short-time MD simulations. We further check the influence of strains present in graphite intercalated compounds(GIC) on the diffusion properties of AlCl_4, and find that their presence in general slows down the diffusion of the intercalated molecule, and is detrimental to the rate performance of the GIC-based battery.     

Optimal aspect ratio of endocytosed spherocylindrical nanoparticle

Recent simulations have demonstrated that bioparticle size and shape modulate the process of endocytosis, and studies have provided more quantitative information that the endocytosis efficiency of spherocylindrical bioparticles is decided by its aspect ratio. At the same time, the dimensions of the receptor-ligand complex have strong effects on the size-dependent exclusion of proteins within the cellular environment. However, these earlier theoretical works including simulations did not consider the effects of ligand-receptor complex dimension on the endocytosis process. Thus, it is necessary to resolve the effects of ligand-receptor complex dimension and determine the optimal aspect ratio of spherocylindrical bioparticles in the process of endocytosis. Accordingly, we proposed a continuum elastic model, of which the results indicate that the aspect ratio depends on the ligand-receptor complex dimension and the radius of the spherocylindrical bioparticle. This model provides a phase diagram of the aspect ratio of endocytosed spherocylindrical bioparticles, the larger aspect ratio of which appears in the phase diagram with increasing ligand density, and highlights the bioparticle design.     

In-Silico Study on the Interaction of Saffron Ligands and Beta-Lactoglobulin by Molecular Dynamics and Molecular Docking Approach

Safranal, crocetin, and dimethylcrocetin are secondary metabolites found in saffron and have a wide range of biological activities. An investigation of their interaction with a transport protein, such as β-lactoglobulin (β-lg), at the atomic level could be a valuable factor in controlling their transport to biological sites. The interaction of these ligands and β-lg as a transport protein was investigated using molecular docking and molecular dynamics (MD) simulation methods. The molecular docking results showed that safranal and crocetin bind on the surface of β-lg. However, dimethylcrocetin binds in the internal cavity of β-lg. The β-lg affinity for binding saffron ligands decreases in the following order: crocetin > dimethylcrocetin > safranal. The analysis of MD simulation trajectories showed that the β-lg and β-lg–ligand complexes became stable at approximately 3000 ps and that there was little conformational change in the β-lg–safranal and β-lg–dimethylcrocetin complexes over a 10-ns timescale. In addition, the profiles of atomic fluctuations showed the rigidity of the ligand binding site during the simulation time.     

Comparison of ligand migration and binding in heme proteins of the globin family

The binding of small diatomic ligands such as carbon monoxide or dioxygen to heme proteins is among the simplest biological processes known. Still, it has taken many decades to understand the mechanistic aspects of this process in full detail. Here, we compare ligand binding in three heme proteins of the globin family, myoglobin, a dimeric hemoglobin, and neuroglobin. The combination of structural, spectroscopic, and kinetic experiments over many years by many laboratories has revealed common properties of globins and a clear mechanistic picture of ligand binding at the molecular level. In addition to the ligand binding site at the heme iron, a primary ligand docking site exists that ensures efficient ligand binding to and release from the heme iron. Additional, secondary docking sites can greatly facilitate ligand escape after its dissociation from the heme. Although there is only indirect evidence at present, a preformed histidine gate appears to exist that allows ligand entry to and exit from the active site. The importance of these features can be assessed by studies involving modified proteins(via site-directed mutagenesis) and comparison with heme proteins not belonging to the globin family.