从头设计蛋白质DS119折叠机制的分子模拟研究

项目名称： 从头设计蛋白质DS119折叠机制的分子模拟研究

项目编号： No.31200548

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 张竹青

作者单位： 中国科学院大学

项目金额： 23万元

中文摘要： 蛋白质从头设计是人们对蛋白质氨基酸残基间相互作用理解的一种检验，其最终目的是设计出具有特定功能的蛋白质，进而应用于生物科技或医药设计。尽管目前设计的蛋白质大多都能在热力学条件下稳定存在，但实验表明它们的动力学折叠过程常表现得和天然蛋白质不同，使得全新设计蛋白质能否象天然蛋白质那样行使功能成为疑问。本项目将以最近从头设计出第一个具有平行beta片层的蛋白DS119为模型，通过全原子分子动力学模拟和分析其折叠过程，通过REMD(replica exchange molecular dynamics)方法得到其折叠热力学自由能曲面；改进基于结构的粗粒化模型，模拟该蛋白质折叠热力学与动力学过程，并与全原子模型得到的结果分析比较，探讨引起其折叠速率慢的可能因素；与其它从头设计蛋白质折叠的研究结果结合，分析设计蛋白质与天然蛋白质折叠不同的一般原因。希望本项目的研究能为蛋白质进一步合理化设计提供新思路。

中文关键词： 从头设计蛋白质；DS119；蛋白质折叠；分子动力学模拟；中间态

英文摘要： Protein de novo design is one of approaches to test the understanding accuracy of interactions between amino acids within protein molecule. Its ultimate purpose is to gain protein with expected function, which could be applied in biotechnology or drug design. Now, most of those de novo designed proteins could fold quite stably under usual thermodynamic condition, but their folding dynamic behaviors display some difference experimentally, comparing to naturally occurring proteins, which leads to the question that if the designed protein could play its role like naturally occurring one. In this project, using protein DS119 as model protein, which is recently de novo designed containing parallel beta-sheet in the first time, we will simulate and analysis its folding process by molecular dynamics in atomic level; obtain its folding free energy landscape by means of REMD (replica exchange molecular dynamics) method; study its folding thermodynamics and kinetics through simulations via improving coarse-grained model, and compare the results with those from atomic level, to find out the possible reasons which lead to its slow folding; together with the studied results of other de novo designed proteins, try to understand general mechanism why they have different folding dynamic characters from naturally occurring ones.

英文关键词： De novo designed proteins；DS119；protein folding；molecular dynamics simulation；intermediate states