Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, USA.
J Phys Chem A. 2010 Apr 8;114(13):4471-85. doi: 10.1021/jp9117776.
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-alpha-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 beta-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 that 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 gamma 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 .
粗粒化分子动力学模拟与全原子方法相比，大大扩展了模拟的时间尺度。在本文中，我们描述了使用基于物理的统一残基（UNRES）力场进行蛋白质结构模拟。我们证明，这种力场提供了约 4000 倍的模拟时间尺度扩展；这一特性既源于对快速移动自由度的平均化，又源于与具有显式溶剂的全原子方法相比，降低了能量和力计算的成本。通过使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折叠模拟时间。通过对葡萄球菌蛋白 A（PDB 代码：1BDD，一个三螺旋束）N 端结构域的示例进行的规范 UNRES/MD 模拟的直接应用，确定了折叠机制并通过数百个或更多轨迹的并行模拟确定了动力学参数。广义系综技术的应用，其中多路复用 replica 交换方法被证明是最有效的，使我们能够计算折叠热力学，并进行基于物理的蛋白质结构的完全预测，其中预测结构是通过在折叠转变温度以下最流行的集合中进行平均来确定的。通过对成核结合蛋白 WW 结构域（PDB 代码：1E0L；一个三股反平行β-折叠）和 1BDD 的 UNRES 折叠轨迹进行主成分分析，我们确定了折叠途径中的代表性结构，并证明只有少数（低指标）主成分可以捕获蛋白质折叠轨迹的主要结构特征；沿着这些基本模式计算的平均力势具有多个最小值，而不是沿着那些沿着其余模式的单峰。此外，与沿着虚拟键二面角γ投影的自由能曲线的剩余模式相比，沿着代表蛋白质折叠的基本集体坐标的自由能曲线中的最小势计算的代表性结构之间的比较揭示了参与不同折叠自由能曲线盆地之间转变的关键残基，与 1E0L 的现有实验数据一致。
