Investigation of protein folding by coarse-grained molecular dynamics with the UNRES force field.
Investigation of protein folding by coarse-grained molecular dynamics with the UNRES force field.
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DOI：
10.1021/jp9117776
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发表时间：
2010-04-08
期刊：
影响因子：
--
通讯作者：
Scheraga HA
中科院分区：
文献类型：
--
作者：
Maisuradze GG;Senet P;Czaplewski C;Liwo A;Scheraga HA
粗粒度的分子动力学模拟提供了一个戏剧性的扩展的时间尺度的模拟相比，全原子的方法。在这篇文章中，我们描述了使用物理为基础的联合残基（UNRES）力场，在我们的实验室，在蛋白质结构模拟。我们证明，这个力场提供了约4000倍的模拟时间尺度的扩展;这一功能产生的快速移动的自由度和减少的能量和力的计算成本相比，所有原子的方法与明确的溶剂。利用大规模并行计算机，可以在几天内获得包含约1000个残基的蛋白质的微秒级折叠模拟时间。以葡萄球菌蛋白A（PDB代码：1BDD，一个三-α-螺旋束）B结构域的N-末端部分为例，一个简单的典型UNRES/MD模拟应用，通过对几百个或更多轨迹的并行模拟，辨别折叠机制并确定动力学参数。使用广义系综技术，其中多路复用的副本交换方法被证明是最有效的，使我们能够计算热力学的折叠和进行完全基于物理的蛋白质结构预测，其中预测的结构被确定为一个平均数在最流行的系综折叠转变温度以下。利用主成分分析法对Formin结合蛋白WW结构域的UNRES折叠轨迹进行了分析，（PDB代码：1 E0 L;一种三链反平行β折叠）和1BDD，我们确定了沿着折叠途径的代表性结构，并证明了只有少数几个（低指数）主成分可以捕获蛋白质折叠轨迹的主要结构特征;与沿着其余的单模态的那些沿着模态相反，沿着沿着这些基本模态计算的平均力的势表现出多个最小值。此外，比较了代表自由能分布图中最小值的结构与蛋白质折叠的基本集体坐标之间的关系，其中自由能分布图沿着（通过主成分分析计算）和自由能分布图沿主链的虚键二面角γ沿着投影，揭示了参与折叠自由能分布图的不同盆之间的转变的关键残基，与1 E0 L的现有实验数据一致。
Coarse-grained molecular-dynamics simulations offer a dramatic extension of the time-scale of simulations compared to all-atom approaches. In this article, we describe the use of the physics-based united-residue (UNRES) force field, developed in our laboratory, in protein-structure simulations. We demonstrate that this force field offers about a 4000-times extension of the simulation time scale; this feature arises both from averaging out the fast-moving degrees of freedom and reduction of the cost of energy and force calculations compared to all-atom approaches with explicit solvent. With massively parallel computers, microsecond folding simulation times of proteins containing about 1000 residues can be obtained in days. A straightforward application of canonical UNRES/MD simulations, demonstrated with the example of the N-terminal part of the B-domain of staphylococcal protein A (PDB code: 1BDD, a three-α-helix bundle), discerns the folding mechanism and determines kinetic parameters by parallel simulations of several hundred or more trajectories. Use of generalized-ensemble techniques, of which the multiplexed replica exchange method proved to be the most effective, enables us to compute thermodynamics of folding and carry out fully physics-based prediction of protein structure, in which the predicted structure is determined as a mean over the most populated ensemble below the folding-transition temperature. By using principal component analysis of the UNRES folding trajectories of the formin-binding protein WW domain (PDB code: 1E0L; a three-stranded antiparallel β-sheet) and 1BDD, we identified representative structures along the folding pathways and demonstrated that only a few (low-indexed) principal components can capture the main structural features of a protein-folding trajectory; the potentials of mean force calculated along these essential modes exhibit multiple minima, as opposed to those along the remaining modes which are unimodal. In addition, a comparison, between the structures that are representative of the minima in the free-energy profile along the essential collective coordinates of protein folding (computed by principal component analysis) and the free-energy profile projected along the virtual-bond dihedral angles γ of the backbone, revealed the key residues involved in the transitions between the different basins of the folding free-energy profile, in agreement with existing experimental data for 1E0L.
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影响因子：
2.8
作者：
Hansmann, UHE
通讯作者：
Hansmann, UHE
影响因子：
4.4
作者：
Altis, Alexandros;Nguyen, Phuong H.;Stock, Gerhard
通讯作者：
Stock, Gerhard
影响因子：
8
作者：
Bai, YW;Karimi, A;Wright, PE
通讯作者：
Wright, PE
影响因子：
56.9
作者：
FRAUENFELDER, H;SLIGAR, SG;WOLYNES, PG
通讯作者：
WOLYNES, PG
DOI：
10.1073/pnas.82.15.5000
发表时间：
1985-01-01
影响因子：
11.1
作者：
ANSARI, A;BERENDZEN, J;YOUNG, RD
通讯作者：
YOUNG, RD