Can molecular dynamics simulations provide high-resolution refinement of protein structure?
Can molecular dynamics simulations provide high-resolution refinement of protein structure?
复制标题
DOI：
10.1002/prot.21345
复制
发表时间：
2007-06-01
影响因子：
2.9
通讯作者：
Brooks, Charles L., III
中科院分区：
文献类型：
--
作者：
Chen, Jianhan;Brooks, Charles L., III
最近的进展，在有效和准确的处理溶剂与广义玻恩近似（GB）已经有可能大大改善蛋白质结构产生的各种预测工具，通过详细的分子动力学模拟。正如最近的CASPR实验所证明的那样，当初始模型足够接近原生盆地时，可以非常可靠地实现改进（例如，3-4埃C-α RMSD）。有效细化的一个关键因素是将可靠的结构信息纳入仿真协议。在不熟悉用于生成初始结构模型的目标和预测方案的情况下，可以假设规则的二级结构元件（螺旋和链）和总体折叠拓扑结构在很大程度上是正确的，使得方案将其自身限制于细化的范围并将采样集中在初始结构附近。二级结构可以通过二面角约束和通过结构接触的拓扑结构来实施，实施为多个成对的C-alpha距离约束或单个侧链距离矩阵约束。的约束是弱的平底电位，以允许足够的灵活性结构重排。通过对高级技术（如副本交换方法（雷克斯））的增强采样，进一步促进了细化。一般来说，对于小到中等大小的单结构域蛋白质，3-5纳秒的雷克斯/GB细化模拟似乎足以实现合理的收敛。对所得结构集合的聚类可以产生更接近C-alpha RMSD中的天然结构的超过1.0埃的精细模型。在大多数情况下，也可以实现侧链接触和旋转异构体状态的实质性改善。对于给定的预测协议，在初始模型中使用更长的采样和对鲁棒结构特征的了解，可以进行额外的改进。然而，在采样以及力场精度方面仍然存在局限性，表现为难以细化长且灵活的回路。Proteins 2007;67：922-930. (C)2007 Wiley-Liss，Inc.
Recent advances in efficient and accurate treatment of solvent with the generalized Born approximation (GB) have made it possible to substantially refine the protein structures generated by various prediction tools through detailed molecular dynamics simulations. As demonstrated in a recent CASPR experiment, improvement can be quite reliably achieved when the initial models are sufficiently close to the native basin (e.g., 3-4 angstrom C-alpha RMSD). A key element to effective refinement is to incorporate reliable structural information into the simulation protocol. Without intimate knowledge of the target and prediction protocol used to generate the initial structural models, it can be assumed that the regular secondary structure elements (helices and strands) and overall fold topology are largely correct to start with, such that the protocol limits itself to the scope of refinement and focuses the sampling in vicinity of the initial structure. The secondary structures can be enforced by dihedral restraints and the topology through structural contacts, implemented as either multiple pair-wise C-alpha distance restraints or a single sidechain distance matrix restraint. The restraints are weakly imposed with flat-bottom potentials to allow sufficient flexibility for structural rearrangement. Refinement is further facilitated by enhanced sampling of advanced techniques such as the replica exchange method (REX). In general, for single domain proteins of small to medium sizes, 3-5 nanoseconds of REX/GB refinement simulations appear to be sufficient for reasonable convergence. Clustering of the resulting structural ensembles can yield refined models over 1.0 angstrom closer to the native structure in C-alpha RMSD. Substantial improvement of sidechain contacts and rotamer states can also be achieved in most cases. Additional improvement is possible with longer sampling and knowledge of the robust structural features in the initial models for a given prediction protocol. Nevertheless, limitations still exist in sampling as well as force field accuracy, manifested as difficulty in refinement of long and flexible loops. Proteins 2007;67:922-930. (C) 2007 Wiley-Liss, Inc.