COMPUTER SIMULATIONS OF PROTEIN STRUCTURE AND DYNAMICS

蛋白质结构和动力学的计算机模拟

• 批准号: 2459337
• 负责人: Ronald Levy
• 金额: $ 26.64万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-06-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2459337
• 关键词: acidity /alkalinity; chemical models; chemical stability; computer simulation; conformation; diamines; dielectric property; ionic bond; lactalbumin; lysozyme; mathematical model; method development; molecular dynamics; nuclear magnetic resonance spectroscopy; protein folding; protein kinase A; protein structure; protein structure function; solutions; solvents; temperature; transforming growth factors

Computer simulations provide the most detailed theoretical method available to study proteins at a molecular level. The proposed research is focused on the development of more accurate methods for molecular dynamics simulations of solvated proteins, and their application to current biophysical problems in the areas of protein electrostatics, dynamics, and folding. The specific goals of this proposal during the next grant period are in two areas: I. the study of protein solvation and electrostatic effects in proteins using explicit solvent models, and II. the study of protein structure and dynamics of native and partially folded states in solution by computer modeling of NMR phenomena. I. The study of protein solvation and electrostatic effects in proteins using explicit solvent models. The current treatment of electrostatic effects in simulations with explicit solvent must be improved. During the next grant period, we will continue our development of methods for treating electrostatic properties in simulations of solvated proteins based on our generalized reaction field (GRF) model and on fast Ewald sum methods. The analysis of pKa shifts in proteins provides a means for understanding pH effects on protein stability and pH dependent conformational changes. We will use the more accurate explicit solvent simulations to predict pKa shifts in a series of well characterized model compounds, including diamines and diacids, and in proteins, including continued work on pKa shifts in lysozyme. A molecular linear response model for predicting charging free energies in solution which we have developed provides us with a powerful analysis tool for this project. II. The study of protein structure and dynamics by computer modeling of NMR phenomena. In a continuing collaboration with experimental NMR groups, we will use simulations to complement experimental NMR studies of protein structure and dynamics. We will focus on (1) the decomposition of NMR order parameters into collective, and more localized motions, (2) analysis of the contributions of protein motions on longer time scales to NMR relaxation, and (3) a comparison between the structure and internal dynamics of fully and partially folded protein. The proteins we will focus on include the human transforming growth factor (hTGFalpha) and alpha-lactalbumin. This work will bring out more clearly the information about functionally important motions contained in NMR relaxation experiments. The alpha-lactalbumin simulations will provide a detailed molecular picture of the structural and dynamical fractures of a partially folded protein to complement NMR experiments.

计算机模拟提供了最详细的理论方法 可用于在分子水平上研究蛋白质。拟议的研究 专注于开发更准确的分子方法 溶剂化蛋白质的动力学模拟及其应用 当前蛋白质静电学领域的生物物理问题， 动力学和折叠。本提案的具体目标 下一个资助期主要集中在两个领域：I.蛋白质溶剂化的研究和 使用显式溶剂模型对蛋白质产生静电效应，以及 II。 天然和部分蛋白质结构和动力学的研究 通过 NMR 现象的计算机建模解决方案中的折叠状态。 一、蛋白质溶剂化和蛋白质静电效应的研究 使用显式溶剂模型。 当前模拟中静电效应的处理 必须改进显式溶剂。在下一个资助期内，我们将 继续开发处理静电特性的方法 基于我们的广义反应模拟溶剂化蛋白质 场（GRF）模型和快速埃瓦尔德和方法。 pKa分析 蛋白质的变化提供了一种了解 pH 值对蛋白质的影响的方法 蛋白质稳定性和 pH 依赖性构象变化。我们将使用 更准确的显式溶剂模拟来预测 pKa 变化 一系列特征良好的模型化合物，包括二胺和 二酸和蛋白质，包括继续研究 pKa 变化 溶菌酶。用于预测免费充电的分子线性响应模型 我们开发的解决方案的能量为我们提供了强大的 该项目的分析工具。 二.通过计算机建模研究蛋白质结构和动力学 核磁共振现象。 在与实验 NMR 小组的持续合作中，我们将使用 模拟以补充蛋白质结构的实验核磁共振研究 和动态。 我们将重点关注（1）NMR阶数的分解 参数转化为集体的、更局部的运动，（2）分析 较长时间尺度上蛋白质运动对 NMR 的贡献 松弛，以及（3）结构和内部的比较 完全和部分折叠蛋白质的动力学。我们将要的蛋白质 重点包括人类转化生长因子（hTGFalpha）和 α-乳白蛋白。这项工作将更清晰地呈现信息 关于 NMR 弛豫中包含的功能性重要运动 实验。 α-乳清蛋白模拟将提供详细的 结构和动态断裂的分子图 部分折叠的蛋白质以补充 NMR 实验。