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Accurate Simulations of Peptide Aggregation

肽聚集的精确模拟

基本信息

批准号：
8135007
负责人：
PAUL E SMITH
金额：
$ 21.46万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-08-31
项目状态：
已结题

项目摘要

It has been established that peptide and protein aggregation lies at the heart of many diseases. Hence, a detailed understanding of exactly when and how peptides or proteins tend to aggregate would be beneficial to a wide range of researchers studying a variety of health related issues. This proposal outlines a program for the systematic study of peptide aggregation using a unique combination of approaches including: currently available experimental thermodynamic data; the theory of preferential interactions as characterized by Kirkwood-Buff (KB) integrals; a simple model for peptide aggregation using preferential interactions between different functional groups in solution; and computer simulation. A theory and model is developed and demonstrated that can decompose and quantify the interactions between different amino acid side chains using existing experimental data on activity coefficients of small peptides, thus enabling predictions of the tendency for aggregation of any small peptide. Computer simulations are proposed to investigate the atomic level details of the aggregation process. A new peptide and protein force field (KBFF) that can reproduce the experimental KB integrals will be completed and used for the simulations. Aim 1. To quantify and characterize the interactions between functional groups observed in peptides. Analysis of existing experimental data will be performed in aqueous solution to determine preferential interaction (PI) parameters for different amino acid and small peptide systems. A simple model of the Pis will be developed and will then be used to isolate and quantify the Pis between different function groups on those peptides. Aim 2. To produce an accurate force field specifically designed for the study of preferential interactions in biomolecular systems. The KBFF approach will be extended to include all amino acid side chains. Aim 3. To understand the role of cosolvents in modifying intermolecular interactions. The addition of cosolvents to a solution of a solute and solvent changes the interactions between the solute molecules. This provides a tool for investigating the strength of intermolecular interactions common in biological systems and how they may be modified. We will focus on the effects of urea and NaCI during our initial studies.

现已证实，多肽和蛋白质聚集是许多疾病的核心。因此，一个详细了解多肽或蛋白质聚集的确切时间和方式将是有益的提供给研究各种健康相关问题的广泛研究人员。这份提案概述了一项计划使用独特的方法组合对多肽聚集进行系统研究，这些方法包括：当前可获得的实验热力学数据；优先相互作用理论柯克伍德-布夫(KB)积分；使用优先相互作用的一个简单的多肽聚集模型溶液中不同官能团之间的相互作用；以及计算机模拟。发展了一种理论和模型。并证明了它可以分解和量化不同氨基酸之间的相互作用链使用现有的小肽的活度系数的实验数据，从而能够预测任何小肽的聚集倾向。计算机模拟被用来研究聚合过程的原子级详细信息。一种新的肽和蛋白质力场(KBFF)，可以复制实验中的Kb积分将完成并用于模拟。目的1.定量和表征多肽中观察到的官能团之间的相互作用。对现有实验数据的分析将在水溶液中进行，以确定优先不同氨基酸和小肽体系的相互作用(PI)参数。Pis Will的一个简单模型然后将用于分离和量化不同官能团之间的PI 那些多肽。目的2.产生一个专门为研究优先相互作用而设计的精确力场生物分子系统。KBFF方法将扩展到包括所有氨基酸侧链。目的3.了解助溶剂在修饰分子间相互作用中的作用。增加了溶质和溶剂溶液中的助溶剂改变了溶质分子之间的相互作用。这提供了一种工具，用于研究生物系统中常见的分子间相互作用的强度如何对它们进行修改。在我们的初步研究中，我们将重点关注尿素和NaCI的影响。