Molecular Dynamics Simulations Of Biological Macromolecu

生物大分子的分子动力学模拟

• 批准号: 6986693
• 负责人: BERNARD R BROOKS
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6986693
• 关键词: chemical models; computer simulation; lipid bilayer membrane; molecular chaperones; molecular dynamics; myosins; nuclear magnetic resonance spectroscopy; peptide structure; protein folding; protein structure function; structural biology

The Computational Biophysics Section studies problems of biological significance using several theoretical techniques: molecular dynamics, molecular mechanics, modeling, ab initio analysis of small molecule structure, and molecular graphics. These techniques are applied to a wide variety of macromolecular systems. Dr. Stan's research has focused on chaperonin-mediated protein folding. Protein folding mediated by chaperonin molecules is studied by computer simulations. Our focus is on the GroEL-GroES chaperonin complex of the Escherichia coli. Annealing action of the GroEL-GroES chaperonin system involves large scale conformational changes which the chaperonin system employs to prevent aggregation or misfolding of proteins. We analyze the structural transformations of GroEL during the cycle by examining the known structures and dynamics of GroEL Identifying natural substrates for chaperonins accomplished by using a sequence-based approach. The E. coli chaperonin machinery GroEL assists the folding of a number of proteins. We describe a sequence-based approach to identify the natural substrate proteins (SPs) for GroEL. Our method is based on the hypothesis that natural SPs are those that contain patterns of residues similar to those found in either GroES mobile loop and/or strongly binding peptide in complex with GroEL. The method is validated by comparing the predicted results with experimentally determined natural SPs for GroEL. We have searched for such patterns in five genomes. In the E. coli genome we identify 1422 (about a third) sequences that are putative natural SPs. A limited analysis of the predicted binding sequences shows that they do not adopt any preferred secondary structure. Our method also predicts the putative binding regions in the identified SPs. The results of our study show that a variety of SPs, associated with diverse functions, can interact with GroEL. Dr. Klauda's research consists of three areas; structural and dynamical behavior of lipids, membrane proteins, and beta-hairpin folding. As a first step in the lipid work, the aliphatic portion of C27 force field was improved (referred to as C27r) using high-level quantum mechanical calculations on alkanes. Molecular dynamics simulations of DPPC bilayers with C27r resulted in improved agreement with experiment compared to the C27 parameter set for gauche populations, NMR deuterium order parameters, and 13C NMR relaxation times. Collaborations with the experimental groups of Prof. John Nagle (Carnegie Mellon University) and Dr. Klaus Gawrisch (NIH/NIAAA) are underway to improve our understanding of structural and dynamical behaviors of lipid bilayers. In addition, the mechanism and protein structural response to sugar transport in lactose permease of E. coli., a membrane protein, is being studied with molecular dynamical simulations of the protein embedded in a POPE bilayer. The final part of Dr. Klauda?s work involves the study of beta-hairpin folding using the Self-Guided Langevin Dyanamics (SGLD) method recently developed. The folding pathways of several design peptides are being studied with explicit solvent and the efficiency of SGLD is being evaluated with explicit solvent. Dr. Zheng's research involves two projects based on the normal modes analysis of a highly simplified elastic network model: 1. We have developed novel computational methods to systematically analyze functionally relevant dynamic correlations within macromolecular complexes: we define two types of dynamic correlations (fluctuations-based and density-based), then we use them to select dynamically important ?hinge residues? and decompose the selected dynamical correlations down to individual normal modes to identify the most relevant modes. We have applied these methods to the analysis of the motor domain of dictyostelium myosin and have obtained interesting results that shed light on its mechanism of force generatioon. 2. We propose a statistical correlation for residues of protein complexes between their dynamical importance to a functionally relevant normal mode (measured by which is computed based on perturbational normal mode analysis of an elastic network model) and their sequential conservation obtained from multiple sequence alignment. We test this relation for a variety of DNA/RNA polymerases, and find it to hold for the open/closed conformational change that is common to them: the clusters of high-dw residues match well with the clusters of conserved residues for a significant portion of the sequence covering the fingers and the palm domains. The clusters of high-dw residues contain conserved residues that are not involved in substrate binding and may be conserved for their dynamic importance to the open/closed conformational change represented by the relevant normal mode. Dr. Che's research involves computer-aided molecular design, which applies principles of ab initio calculations and molecular dynamics simulations to the deign and development of bioactive agents such as drugs. The projects include successful design of following small molecules to act as protein secondary structure mimetics. For inhibiting protein-protein binding, general methods for mimicking protein surface structures would represent a significant advances. Protein binding interfaces comprise alpha-helix, beta-sheet, turns, polyproline structures, and loops secondary structures in an apparently unbiased manner, thus we have designed small molecules that can mimic each of these structures. Dr. Woodcock's research involves the investigation of carbohydrate structure, specifically the conformational properties of glucose analogs and examining the effects that solvation has on these systems. A collaboration with the group of Dr. Daron Freedberg and involves investigating the structural parameters of glucose (determined via NMR) and exploring the various effects that lead to the observed structural characteristics.

计算生物物理学部分使用几种理论技术研究具有生物学意义的问题：分子动力学、分子力学、建模、小分子结构的从头计算分析和分子图形学。这些技术被广泛应用于各种大分子体系。 斯坦博士的研究重点是伴侣蛋白介导的蛋白质折叠。通过计算机模拟研究了分子伴侣介导的蛋白质折叠。我们的重点是大肠杆菌的GroEL-Groes伴侣蛋白复合体。GroEL-Groes伴侣蛋白系统的退火作用涉及到大规模的构象变化，伴侣蛋白系统利用这些变化来防止蛋白质的聚集或错误折叠。我们通过研究GroEL的已知结构和动力学，分析了GroEL在周期中的结构变化，并通过基于序列的方法确定了伴侣蛋白的天然底物。大肠杆菌伴侣蛋白机制GroEL帮助许多蛋白质的折叠。我们描述了一种基于序列的方法来鉴定GroEL的天然底物蛋白(SP)。我们的方法是基于这样的假设，即天然SP包含的残基模式类似于GroES移动环和/或与GroEL形成的络合物中的强结合肽。通过将预测结果与实验测定的GroEL的自然SPS进行比较，验证了该方法的有效性。我们已经在五个基因组中寻找了这样的模式。在大肠杆菌基因组中，我们鉴定了1422个(约三分之一)序列，这些序列可能是天然的SP。对预测的结合序列的有限分析表明，它们没有采用任何优选的二级结构。我们的方法还预测了已识别的SP中的假定结合区域。我们的研究结果表明，与不同功能相关的各种SP可以与GroEL相互作用。 Klauda博士的研究包括三个领域：脂类的结构和动力学行为、膜蛋白和β-发夹折叠。作为脂质工作的第一步，通过对烷烃进行高水平量子力学计算，改进了C27力场的脂肪部分(称为C27r)。用C27r对DPPC双层膜进行的分子动力学模拟结果表明，与C27参数集相比，C27参数集、核磁共振氢序参数和13C核磁共振弛豫时间与实验符合得更好。与卡内基梅隆大学的John Nagle教授和NIH/NIAAA的Klaus Gawrisch博士的实验小组的合作正在进行中，以提高我们对脂双层结构和动力学行为的理解。此外，利用Pope双层包埋蛋白的分子动力学模拟，研究了膜蛋白E.Coli.的乳糖渗透酶对糖转运的机制和蛋白质结构的响应。Klauda？S博士工作的最后部分涉及使用最近发展的自导朗之万动力方法研究β-发夹折叠。用显性溶剂研究了几种设计多肽的折叠途径，用显性溶剂评价了SGLD的效率。 郑博士的研究涉及两个基于高度简化的弹性网络模型的简正模式分析的项目： 1.我们开发了新的计算方法来系统地分析大分子复合体中功能相关的动态关联：我们定义了两种类型的动态关联(基于涨落和基于密度)，然后用它们来选择动态重要的铰链残基？并将所选择的动态关联分解为各个正常模式，以识别最相关的模式。我们已将这些方法应用于Dictyostelialmyosin的运动域的分析，并取得了有趣的结果，为揭示其力的产生机制提供了线索。 2.我们提出了蛋白质复合体残基的统计关联，即它们对功能相关简正模的动力学重要性(通过弹性网络模型的微扰简正模分析来计算)和它们从多序列比对获得的序列保守性之间的统计关联。我们对各种DNA/RNA聚合酶进行了测试，发现这种关系适用于它们共同的开放/闭合构象变化：高dW残基的簇与覆盖手指和手掌结构域的序列的很大一部分的保守残基簇匹配得很好。高dW残基的簇包含保守的残基，这些残基不参与底物结合，并且可能因为它们对相关正常模式所代表的开放/闭合构象变化的动力学重要性而保守。 车博士的研究涉及计算机辅助分子设计，它将从头计算和分子动力学模拟的原理应用于药物等生物活性物质的设计和开发。这些项目包括成功设计以下小分子作为蛋白质二级结构模拟物。在抑制蛋白质-蛋白质结合方面，模拟蛋白质表面结构的一般方法将是一个重大的进展。蛋白质结合界面包括α-螺旋、β-折叠、转角、多聚脯氨酸结构和环状二级结构，因此我们设计了能够模拟这些结构的小分子。 Woodcock博士的研究涉及对碳水化合物结构的研究，特别是葡萄糖类似物的构象特性，并检查溶剂化对这些系统的影响。与Daron Freedberg博士的团队合作，研究葡萄糖的结构参数(通过核磁共振确定)，并探索导致观察到的结构特征的各种影响。