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Developing a new protein homology-modeling method with high precision

开发一种新的高精度蛋白质同源建模方法

基本信息

批准号：
16201043
负责人：
NISHIKAWA Ken
金额：
$ 23.63万
依托单位：
National Institute of Genetics
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

This study aimed to develop a protein-structure modeling method that can reproduce the native 3D structure of a target protein starting from a model structure obtained by the usual homology-modeling method. Employing the latest computational theories, the resulting full-atom protein model structure would be as precise as that determined by the X-ray crystallography (i.e., 2A or better in the atomic resolution). In order to realize this sort of method, there are two main problems to be solved. One is a so-called force-field problem, in which the X-ray structure does not correspond to the minimum energy point when the conformation energy is calculated with the existing force fields. The other is a sampling problem in the structural space of a protein, where energy minimization should be carried out overcoming high energy barriers as going one minimum point to another.For the first problem above, a statistical potential system was developed from the database analysis for backbone dihedral … More angles of all 20 amino acids, and this potential system was incorporated into the AMBER force fields in place of the corresponding energy terms. The modified AMBER system provided significantly better results in terms of the minimum energy point relative to the X-ray structure. For the second problem, we extended the usual multicanonical theory by employing the Wang-Landau theory. Replacing the Monte Carlo procedure originally used in the latter theory with the molecular dynamics, we developed a Wang-Landau Molecular Dynamic (WL MD) technique, which enabled automatic estimation of weighting factors during the molecular simulation. In this way, the difficulty in the conventional multicanonical method was overcome, and fast and efficient search in the structural space was realized. The new method was applied to folding simulation of a small-sized protein (Trp-Cage), in comparison with that by the standard replica exchange MD (RE-MD) method. The results showed clearly better efficiency with the WL-MD method than that with RE-MD. Less

本研究旨在开发一种蛋白质结构建模方法，该方法可以从通常的同源建模方法获得的模型结构开始，再现目标蛋白质的天然3D结构。采用最新的计算理论，得到的全原子蛋白质模型结构将与x射线晶体学确定的结构一样精确（即原子分辨率为2A或更高）。为了实现这种方法，有两个主要问题需要解决。一种是所谓的力场问题，即用现有力场计算构象能时，x射线结构并不对应于最小能点。另一个是蛋白质结构空间中的采样问题，在从一个最小点到另一个最小点的过程中，需要克服高能量障碍来实现能量最小化。针对上述第一个问题，通过对所有20种氨基酸的主二面体多角度的数据库分析，建立了一个统计势体系，并将该势体系纳入AMBER力场中，代替相应的能量项。改进后的AMBER系统在相对于x射线结构的最小能量点方面提供了明显更好的结果。对于第二个问题，我们采用王-朗道理论扩展了通常的多范式理论。本文提出了一种基于分子动力学的Wang-Landau分子动力学（WL MD）技术，该技术可以在分子模拟过程中自动估计权重因子。该方法克服了传统多范式方法的不足，实现了结构空间的快速高效搜索。将该方法应用于小尺寸蛋白质（Trp-Cage）的折叠模拟，并与标准复制交换MD （RE-MD）方法进行了比较。结果表明，WL-MD法的效率明显优于RE-MD法。少