BIOMOLECULAR KINETICS VIA DYNAMIC IMPORTANCE SAMPLING

通过动态重要性采样进行生物分子动力学

• 批准号: 6518839
• 负责人: DANIEL M ZUCKERMAN
• 金额: $ 1.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6518839
• 关键词: chemical kinetics; chemical models; computer simulation; conformation; dipeptides; fatty acid binding protein; molecular dynamics; protein structure; stereochemistry; thermodynamics

We propose to extend a new computational technique, "Dynamic Importance Sampling" (DIMS) to the study conformational transitions in peptides and proteins. Our long term goals are to study the kinetics and thermodynamics of a type VI turn and, ultimately, of the fatty acid binding protein (FABP). These systems ideal subjects for the DIMS technique because the three-dimensional structures of the different states conformational states in the type VI turn and ligand bound/unbound states in FABP) are known. From such known start and end structures, DIMS is capable of computing (a) reaction rates, (b) transition paths, and equilibrium state populations. The method has proved efficient in small systems because it gathers all necessary information on the very short timescale in which a transition event (i.e., barrier crossing) occurs, rather than on the much longer timescale between transitions - which limits many traditional techniques like molecular dynamics. Our specific aims are to compute (a) - (c) for the following all-atom systems, modeled by the AMBER potential in the "Molecular Modelling Toolkit": (I) isomerizations in implicitly-solvated butane alanine dipeptide; (II) isomerizations in butane and alanine dipeptide in explicit water; (III) conformational transitions for a type VI turn; and, (IV) fatty acid entrance and exit in FABP.

我们提出了一种新的计算技术，“动态重要性采样”（DIMS）的研究多肽和蛋白质的构象转变。 我们的长期目标是研究VI型转向的动力学和热力学，并最终研究脂肪酸结合蛋白（FABP）。这些系统是DIMS技术的理想对象，因为不同状态的三维结构（VI型转弯中的构象状态和FABP中的配体结合/未结合状态）是已知的。根据这种已知的起始和终止结构，DIMS能够计算（a）反应速率、（B）转变路径和平衡态布居。该方法已被证明在小型系统中是有效的，因为它在非常短的时间尺度上收集所有必要的信息，在该时间尺度中，转换事件（即，势垒跨越）发生，而不是在跃迁之间的更长时间尺度上发生-这限制了许多传统技术，如分子动力学。我们的具体目标是计算以下全原子系统的（a）-（c），由“分子建模工具包”中的AMBER势建模：（I）在隐式溶剂化丁烷丙氨酸二肽的异构化;（II）在显式水中丁烷和丙氨酸二肽的异构化;（III）VI型转弯的构象转变;以及（IV）脂肪酸在FABP中的入口和出口。