Molecular Dynamics Simulations Of Biological Macromolecu

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。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多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复合体的分子动力学 -C3a过敏毒素和抗体结合部位 -人鼻病毒中蛋白质结构的稳定性和活性 -用QM/MM方法模拟腺苷激酶的催化机理 -用QM/MM方法研究D5-3-酮类固醇异构酶的催化机理 -用QM/MM方法研究N-乙酰转移酶的催化机理 -用QM/MM方法研究氯酸变位酶的催化机理 -追踪β-内酰胺水解的催化途径 -确定人类基因NFAT5的编码区和启动子区域。 -探索确定一组蛋白质序列的相互关联性的方法。 -辛基糖苷胶束的模拟 -将辛基葡萄糖苷模拟扩展到黄蜂毒肽Mastoparan X -确定果蝇13,500个基因中哪些编码信号肽 基础研究正在进行中，以更好地了解大分子系统。这些项目包括以下方面的研究： -伴侣蛋白介导的蛋白质折叠 --核磁共振屏蔽张量计算 -脂类双层凝胶相模拟 --研究核酸结构的环境依赖性 -建模亮氨酸拉链：线圈的平行和反平行方向的起源 -肌红蛋白和溶菌酶晶体和溶液的模拟 -Cl2的分子动力学模拟 用计算机模拟的方法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，其相关结构已知。使用了高性能的科学计算方法，例如蛋白质的粗粒度和全原子描述，以及最先进的CHARMM模拟程序。这些研究将阐明伴侣对蛋白质结构的影响，伴侣系统的机制，以及伴侣周期中的时间尺度。 用从头算方法计算了1H和15N原子核的核磁共振屏蔽张量，并与实验结果进行了比较。酰胺1H的计算值与实验值之间的相关性很小，研究了基组和同位素效应等因素的作用是造成差异的潜在原因。目前正在进行一项15N研究，以1H结果为起点。 在生理条件和连续体模型下用分子动力学(MD)计算酵母转录因子Gcn4的亮氨酸拉链结构域(Gcn4-p1)的自由能。亮氨酸拉链图案是一个平行的左手超级线圈，由两个a-螺旋组成。据估计，自然(平行)取向在能量上比非自然反平行取向更稳定，在非自然反平行取向中，静电能在两种取向的总能量图中都有很大的贡献，而且对平行取向和反平行取向的偏好也有很大贡献。 腺苷被三磷酸腺苷磷酸化是由腺苷激酶催化的。通过使用量子力学/分子力学技术，人们正在研究出这一机制可以继续进行的不同途径。用我们的高斯模糊双键原子方法，计算了腺苷5‘醇的酸性和天冬氨酸的质子亲和力。这些都是整个机制中的关键步骤，并使人们相信我们的QM/MM方法将在研究整个系统时提供合理的答案。 用全原子模型和显式水进行SGMD模拟，研究蛋白质折叠机制。我们成功地观察到了蛋白质的双态折叠现象。

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 - C3a anaphylatoxin and antibody binding sites - Protein structure stabilization and activity in human rhinovirus - Modeling the catalytic mechanism of adenosine kinase with QM/MM methods - 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 - Determine the coding and promoter regions for the human gene NFAT5. - exploring methods for determining the inter-relatedness of a group of protein sequences. - Simulations of octyl glucoside micelles - Extend octyl glucoside simulations to the peptide Mastoparan X, a wasp venom - Determining which of the 13,500 genes in the Drosophila code for signal peptides Basic research is underway to provide a better understanding of macromolecular systems. The projects include studies of: - Chaperonin-mediated protein folding - NMR Shielding Tensor calculations - Lipid bilayer gel phase simulations - Investigating the environmental dependence of nucleic acid structure - Modeling leucine zippers: Origins of parallel vs. antiparallel orientation of coiledcoils - Simulations of myoglobin and lysozyme crystals and solutions - Molecular dynamics simulations of CI2 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 will shed light on 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. The phosphorylation of adenosine by ATP is catalyzed by Adenosine Kinase. The different pathways in which the mechanism can proceed are being worked out by using quantum mechanical/molecular mechanical techniques. Using our double link atom method with gaussian blur, we have calculated the acidity of the 5' alcohol of adenosine and the proton affinity of aspartate. These are crucial steps in the overall mechanism and provides confidence that our QM/MM method will provide reasonable answers while studying the entire system. Studying protein folding mechanism through SGMD simulation with all-atom model and explicit water. We have successfully observed two-state protein folding phenomena.