Folding free-energy landscape of villin headpiece subdomain from molecular dynamics simulations
Folding free-energy landscape of villin headpiece subdomain from molecular dynamics simulations
复制标题
DOI：
10.1073/pnas.0608432104
复制
发表时间：
2007-03-20
影响因子：
11.1
通讯作者：
Duan, Yong
中科院分区：
文献类型：
--
作者：
Lei, Hongxing;Wu, Chun;Duan, Yong
尽管经过几十年的努力，高精度从头折叠仍然是一个难以捉摸的目标。为了探索绒毛头部子结构域HP 35的折叠景观，我们进行了两套副本交换分子动力学为200 ns的每一个和三套传统的微秒长的分子动力学模拟，使用AMBER FF 03力场和广义玻恩溶剂化模型。蛋白质折叠一致的天然状态;最低的C-α-rmsd从x射线结构是0.46埃，和C-α-rmsd的中心的人口最多的集群是1.78埃在300 K。从头算模拟以前没有达到这个水平。HP 35的折叠景观可以分为天然区域、变性区域和两个中间态区域。天然状态是由一个小的障碍，而一个大的障碍之间存在的主要折叠的中间状态和变性状态。从热容曲线中提取的熔化温度T-m = 339 K与实验得出的T = 342 K非常一致。一个全面的图片HP 35折叠的动力学和热力学出现时，从副本交换和传统的分子动力学模拟的结果相结合。
High-accuracy ab initio folding has remained an elusive objective despite decades of effort. To explore the folding landscape of villin headpiece subdomain HP35, we conducted two sets of replica exchange molecular dynamics for 200 ns each and three sets of conventional microsecond-long molecular dynamics simulations, using AMBER FF03 force field and a generalized-Born solvation model. The protein folded consistently to the native state; the lowest C-alpha-rmsd from the x-ray structure was 0.46 angstrom, and the C-alpha-rmsd of the center of the most populated cluster was 1.78 angstrom at 300 K. ab initio simulations have previously not reached this level. The folding landscape of HP35 can be partitioned into the native, denatured, and two intermediate-state regions. The native state is separated from the major folding intermediate state by a small barrier, whereas a large barrier exists between the major folding intermediate and the denatured states. The melting temperature T-m = 339 K extracted from the heat-capacity profile was in close agreement with the experimentally derived T = 342 K. A comprehensive picture of the kinetics and thermodynamics of HP35 folding emerges when the results from replica exchange and conventional molecular dynamics simulations are combined.