Mechanism of the CD2/CD58 complex formation in immune system

免疫系统中CD2/CD58复合物形成机制

基本信息

批准号：
11680657
负责人：
KITAO Akio
金额：
$ 2.3万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680657/
关键词：
CD2 CD58 Complex formation NMR Structural refinement Binding free energy Dynamics Molecular dynamics

项目摘要

The mechanism of the CD2/CD58 complex formation was investigated by computer simulation. Our purposes of this project are 1) Investigate protein dynamics involved with the complex formation, 2) Estimate contribution from amino acid residues and energy terms by free energy analysis, 3) Investigate the role of CD2/CD58 complex formation in signal transfer. In order to attain the first purpose, a novel method has been developed in order to refine structure and dynamic of proteins in solution by using NMR restraints and relaxation parameters. This method is based on the concept of Jumping-Among-Minima (JAM) model: In this model we assume that protein dynamics consists of two types of motions, intra-substate motion and inter-substate motion. Intra-substate motions, which occur in the time scale of~ 10 psec, are simulated with molecular dynamics calculations with force field energy terms. Inter-substate motions are included by creating an ensemble of structures consistent with the geometric … More NMR restraints. Statistical weights of the conformational substates are determined to reproduce the NMR relaxation parameters. The motions affect primarily the curvature of the slightly concave counter-receptor-binding site and represent transitions between a concave (closed) and flat (open) binding face. By comparing the ensemble of structures in solution to the complex structure with counter receptor CD58, we found that these two types of transitions resemble the change upon counter-receptor binding. To achieve the second purpose, we have developed the REUS (Replica Exchange Umbrella Sampling) to carry out free energy calculation. This method is the combination of the replica exchange method and WHAM (Weighted Histogram Analysis Method). This enables us to estimate binding free energy more accurately. Free energy analysis of various mutations are being carried out but not yet finished. We are planning to continue this kind of calculation to further investigate the signal transfer mechanisms in immune system. Less

通过计算机模拟研究了 CD2/CD58 复合物形成的机制，我们该项目的目的是 1) 研究与复合物形成相关的蛋白质动力学，2) 通过自由能分析估计氨基酸残基和能量项的贡献，3)研究 CD2/CD58 复合物形成在信号传递中的作用为了实现第一个目的，我们开发了一种新方法，通过使用 NMR 约束和弛豫参数来细化溶液中蛋白质的结构和动态。基于跳跃极小值（JAM）模型的概念：在该模型中，我们假设蛋白质动力学由两种类型的运动组成，即子状态内运动和子状态内运动，它们发生在时间上。尺度约为 10 皮秒，通过创建与构象的几何 NMR 统计重量一致的结构集合，通过力场能量项进行模拟。通过比较结构的整体，确定子状态以重现 NMR 弛豫参数。为了解决反受体CD58的复杂结构，我们发现这两种类型的转变类似于反受体结合时的变化。为了实现第二个目的，我们开发了REUS（复制交换伞）。采样）进行自由能计算，该方法是副本交换法和WHAM（加权直方图分析法）的结合，这使得我们能够更准确地估计各种突变的自由能分析。尚未完成。我们计划继续这种计算，以进一步研究免疫系统中的信号传递机制。