Molecular Dynamics Simulations Of Biological Macromolecu

生物大分子的分子动力学模拟

• 批准号: 6690469
• 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/6690469
• 关键词: adenosine kinase; anaphylatoxins; antigen antibody reaction; chemical models; computer simulation; enzyme mechanism; homeobox genes; lipid bilayer membrane; molecular chaperones; molecular dynamics; myoglobin; protein folding; protein structure function; quantum chemistry; rhinovirus; transcription factor; virus protein

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. Specific projects applied to molecules of biomedical interest uses molecular dynamics simulations to predict function or structures of peptides and proteins. Such projects include: - Molecular dynamics of native and mutant vnd/NK-2 homeodomain--DNA complexes - Protein structure stabilization and activity in human rhinovirus - Modeling of Acanthamoeba Myosin II wildtype leucine zipper segment - The study of the catalytic mechanism of D5-3-Ketosteroid Isomerase using QM/MM methods - The study of the catalytic mechanism of N-acetyltransferase using QM/MM methods - The study of the catalytic mechanism of Chorismate Mutase using QM/MM methods - Tracing the catalytic pathway of b-lactam hydrolysis Basic research is underway to provide a better understanding of macromolecular systems. The projects include studies of: - Examining chaperonin-mediated protein folding - NMR Shielding Tensor calculations - Lipid bilayer gel phase simulations - Investigating the environmental dependence of nucleic acid structure - Free energy calculations on the leucine zipper domain of yeast transcription factor GCN4 - Simulations of myoglobin and lysozyme crystals and solutions - Protein folding simulation studies - Solvation Free energy force of protein systems - Ligand binding dynamics - Microscopic details of rotational diffusion of perylene in organic solvents The annealing action of the GroEL/GroES chaperonin system is the result of changes in the microenvironment felt by substrate proteins. We analyzed the GroEL structural transformations during the cycle by examining known structures of GroEL (T state), GroEL-7ATP (R) and GroEL-GroES-7ADP (R"). We find that large structural changes occur even prior to GroES binding, and are associated mostly with residues in the apical domain. Multiple sequence alignments show a strong conservation of the chemical character, rather than the residue type, of residues important for the chaperonin functions. We predict that mutations in several strongly conserved charged residues (Lys 262, Gly 252, and Asp 253) lead to reduced efficiency of the annealing action. Molecular dynamics simulations of a solvated apical domain, liganded to a 12-mer polypeptide or unliganded, yield information about the solvent effects and the chaperonin structural dynamics. Upon polypeptide binding, water is completely removed from the peptide binding site. The apical domain manifests a high flexibility at a pair of parallel helices, which execute a transverse translation to accommodate the peptide. Protein folding mediated by chaperonin molecules is studied using computer simulations. Our focus is on the GroEL-GroES chaperonin complex of the Escherichia coli, for which the associated structures are known. High-performance scientific computing methods are used, such as coarse-grained and all-atom descriptions of proteins in conjunction with the state-of-the-art CHARMM simulation program. These studies elucidate the effect of chaperones on the protein structure, the mechanism of the chaperonin system, and the timescales in the chaperonin cycle. Ab initio calculations of NMR shielding tensors were performed for comparison with experimental studies for 1H and 15N nuclei. There was little correlation between calculated and experimental values for amide 1H, and role of factors such as basis set, and isotope effect were investigated as potential causes for the discrepancy. An 15N study is currently underway, using the 1H results as a starting point. Free energy calculations on the leucine zipper domain (GCN4-p1) of the yeast transcription factor GCN4 using Molecular Dynamics (MD) under physiological conditions and continuum models. The leucine zipper motif is a parallel left-handed supercoil composed of two a-helices. It is estimated that the native (parallel) alignment is energetically more stable than the non-native antiparallel alignment where electrostatic energies contribute significantly in the overall energetic picture of both orientation as well as to the preference of the parallel vs the antiparallel orientation. Modeling of Acanthamoeba Myosin II wildtype leucine zipper segment using molecular dynamics. This type of analysis has been extended to the modeling of acanthamoeba myosin II wildtype leucine zipper segment using molecular dynamics which examines free energy of solvation and helical packing, while evaluating different alignments of the myosin II wildtype leucine zipper segment. The results suggest likely mechanism for previously unexplained protein mutation behavior. Protein mechanisms are studied by examining different possible pathways in which the mechanism can proceed. This employs quantum mechanical/molecular mechanical techniques using our double link atom method with gaussian blur of MM charges. We have carried out QM/MM simulations N-acetyltransferase to determine whether a proton of the primary amine of serotonin is transferred via a water channel or His120 during catalysis. Similarly, we have examined D5-3-Ketosteroid Isomerase. This enzyme catalyzes the isomerization of the 5,6 double bond of D5-3-ketosteroid isomerase to the 4,5 position. In particular, examine h-bonding interactions between substrate D5-3-ketosteroid and the key residues, Tyr14 and Asp99 at both QM/MM and MM level. Studying protein folding mechanism through SGMD simulation with all-atom model and explicit water. We have successfully observed two-state protein folding phenomena. This method have proved useful in the rapid exploration of conformational space without resorting to higher temperature simulations, or other forcing potentials.

计算生物物理学部分使用几种理论技术研究生物学意义的问题：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。这些技术适用于各种各样的大分子系统。 应用于生物医学感兴趣的分子的特定项目使用分子动力学模拟来预测肽和蛋白质的功能或结构。这些项目包括： - 天然和突变型vnd/NK-2同源结构域-DNA复合物的分子动力学 - 人鼻病毒的蛋白质结构稳定性和活性 - 阿米巴肌球蛋白II野生型亮氨酸拉链片段的模型化 - 用QM/MM方法研究D5-3-酮类异构酶的催化机理 - QM/MM方法研究N-乙酰转移酶的催化机理 - 用QM/MM方法研究Chorismate Mutase的催化机理 - β-内酰胺水解催化途径的追踪 基础研究正在进行中，以更好地了解大分子系统。这些项目包括研究： - 检测伴侣蛋白介导的蛋白质折叠 - NMR屏蔽张量计算 - 脂质双层凝胶相模拟 - 研究核酸结构的环境依赖性 - 酵母亮氨酸拉链结构域的自由能计算 转录因子GCN 4 - 肌红蛋白和溶菌酶晶体和溶液的模拟 - 蛋白质折叠模拟研究 - 蛋白质体系的溶剂化自由能力 - 配体结合动力学 - 苝在有机溶剂中旋转扩散的微观细节 GroEL/GroES伴侣蛋白系统的退火作用是以下作用的结果： 底物蛋白感受到的微环境变化。我们分析 通过检查已知的GroEL结构转换周期 GroEL（T状态）、GroEL-7ATP（R）和GroEL-GroES-7ADP（R”）的结构。 我们发现，大的结构变化甚至发生在GroES结合之前， 并且主要与顶端结构域中的残基相关。多 序列比对显示化学特征具有很强的保守性， 而不是残基类型，对于伴侣蛋白重要的残基 功能协调发展的我们预测，在几个强保守的带电突变， 残基（Lys 262，Gly 252和Asp 253）导致降低的效率， 退火作用。分子动力学模拟的溶剂化顶端域，配体的12聚体多肽或unliganded，产生有关溶剂的影响和伴侣蛋白的结构动力学信息。在多肽结合时，水从肽结合位点完全除去。顶端结构域在一对平行螺旋处表现出高柔性，其执行横向翻译以容纳肽。 利用计算机模拟研究了伴侣蛋白分子介导的蛋白质折叠。我们的重点是大肠杆菌的GroEL-GroES伴侣蛋白复合物，其相关结构是已知的。使用高性能的科学计算方法，例如结合最先进的CHARMM模拟程序对蛋白质进行粗粒度和全原子描述。这些研究阐明了分子伴侣对蛋白质结构的影响，分子伴侣系统的机制，以及分子伴侣循环的时间尺度。 对1H和15 N核的NMR屏蔽张量进行了从头计算，并与实验结果进行了比较。酰胺1H的计算值和实验值之间几乎没有相关性，并研究了基组和同位素效应等因素的作用作为差异的潜在原因。目前正在进行一项15 N研究，以1H结果为起点。 在生理条件和连续介质模型下用分子动力学方法计算酵母转录因子GCN 4的亮氨酸拉链结构域（GCN 4-p1）的自由能。亮氨酸拉链基序是由两个α-螺旋组成的平行左手超螺旋。据估计，本机（平行）的对齐是积极更稳定的非本地反平行对齐，其中静电能有助于显着的整体充满活力的图片的两个方向，以及平行与反平行方向的偏好。 利用分子生物学方法模拟阿米巴肌球蛋白II野生型亮氨酸拉链片段 分子动力学这种类型的分析已被扩展到棘阿米巴肌球蛋白II野生型亮氨酸拉链段的建模，使用分子动力学检查溶剂化和螺旋包装的自由能，同时评估不同的对齐的肌球蛋白II野生型亮氨酸拉链段。这些结果表明了以前无法解释的蛋白质突变行为的可能机制。 蛋白质机制通过检查机制可以进行的不同可能途径来研究。这采用了量子力学/分子力学技术，使用我们的双链接原子方法与高斯模糊的MM收费。我们已经进行了QM/MM模拟N-乙酰转移酶，以确定是否通过水通道或His 120在催化过程中转移的一个质子的伯胺的5-羟色胺。同样，我们已经检查了D5-3-酮类固醇异构酶。该酶催化D5-3-酮类甾体异构酶的5，6双键异构化至4，5位。特别是，在QM/MM和MM水平上检查底物D5-3-酮类类固醇与关键残基Tyr 14和Asp 99之间的氢键相互作用。 采用全原子模型和显式水相结合的SGMD方法研究蛋白质折叠机理。我们已经成功地观察到了两态蛋白质折叠现象。这种方法已被证明是有用的，在快速探索构象空间，而不诉诸更高的温度模拟，或其他强迫势。