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: 6525705
• 负责人: Ronald Levy
• 金额: $ 29.56万
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525705
• 关键词: biophysics; chemical models; chemical stability; computer simulation; conformation; dielectric property; ionic bond; lactalbumin; mathematical model; method development; model design /development; molecular dynamics; molecular polarity; nuclear magnetic resonance spectroscopy; protein binding; protein structure function; solutions; solvents; thermodynamics

The goal of this research is the development of more accurate methods for molecular dynamics simulations of solvated proteins, and their application to problems in biophysical chemistry involving the modeling of protein electrostatic effects in solution, the thermodynamics of ligand binding to proteins, and the long time dynamics of proteins. There are four specific aims: 1. Characterize protein dielectric properties using detailed atomic simulations: Qualitative and quantitative improvements are needed in the models currently used to predict electrostatic properties that govern protein activity and stability. We will develop a consistent framework for modeling protein dielectric properties that can bridge the current gap between continuum and explicit solvent viewpoints. 2. Determine the energy and entropy components of protein-ligand binding free energies Free energy simulations have been applied to determine the chemical potentials of solutes in water and to determine the binding free energies of ligands to proteins, but the corresponding enthalpy and entropy changes have not been analyzed because of stringent computer requirements and theoretical hurdles. Binding enthalpies and entrophies provide important information to help understand binding reactions. We will extend methods we recently developed to extract enthalpies and entrophies from free energy simulations of organic solutes in water to protein-ligand binding reactions. We will explore the role of active site and ligand flexibility in the binding thermodynamics. 3. Develop implicit solvent model of molecular dynamics simulations of solvated proteins The computational speed of implicit solvent models makes them attractive for use in molecular dynamics simulations of solvated proteins when either extensive conformational sampling or long simulation times are required. We will develop an implicit solvent model based on the Generalized Born framework which can be used in molecular dynamics simulations of proteins. 4. Study protein dynamics using computer simulations and the modeling of NMR phenomena. We will continue our collaboration with NMR groups on the study of protein dynamics. This includes the further development of more sophisticated statistical methods to extract dynamical parameters from NMR relaxation experiments and the development of efficient methods for simulating the long time dynamics of proteins using the Generalized Born implicit solvent model and Langevin equations of motion.

本研究的目标是开发更准确的方法，溶剂化蛋白质的分子动力学模拟，并将其应用于生物物理化学中的问题，包括蛋白质静电效应在溶液中的建模，配体与蛋白质结合的热力学，以及蛋白质的长时间动力学。 具体目标有四个：1。使用详细的原子模拟表征蛋白质的介电特性：目前用于预测蛋白质活性和稳定性的静电特性的模型需要进行定性和定量改进。 我们将开发一个一致的框架，蛋白质介电特性建模，可以弥合目前的差距连续和明确的溶剂的观点。 2.确定蛋白质-配体结合自由能的能量和熵成分自由能模拟已被应用于确定水中溶质的化学势和确定配体与蛋白质的结合自由能，但由于严格的计算机要求和理论障碍，相应的焓变和熵变尚未被分析。 结合熵和结合熵为理解结合反应提供了重要的信息。 我们将扩展我们最近开发的方法，以从水中有机溶质的自由能模拟中提取蛋白质-配体结合反应的熵和熵。 我们将探讨结合热力学中活性位点和配体柔性的作用。 3.开发溶剂化蛋白质分子动力学模拟的隐式溶剂模型隐式溶剂模型的计算速度使得它们在需要大量构象采样或长模拟时间的溶剂化蛋白质分子动力学模拟中具有吸引力。 我们将发展一个基于广义玻恩框架的隐式溶剂模型，它可以用于蛋白质的分子动力学模拟。 4.使用计算机模拟和NMR现象建模研究蛋白质动力学。我们将继续与NMR小组合作研究蛋白质动力学。 这包括进一步发展更复杂的统计方法来提取动力学参数NMR弛豫实验和开发有效的方法来模拟蛋白质的长时间动态使用广义玻恩隐式溶剂模型和Langevin运动方程。