Xun Sangni, Jiang Fan, Wu Yun-Dong
Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen, 518055, China.
College of Chemistry and Molecular Engineering, Peking University , Beijing, 100871, China.
J Chem Theory Comput. 2015 Apr 14;11(4):1949-56. doi: 10.1021/acs.jctc.5b00029. Epub 2015 Mar 12.
An important application of all-atom explicit-solvent molecular dynamics (MD) simulations is the refinement of protein structures from low-resolution experiments or template-based modeling. A critical requirement is that the native structure is stable with the force field. We have applied a recently developed residue-specific force field, RSFF1, to a set of 30 refinement targets from recent CASP experiments. Starting from their experimental structures, 1.0 μs unrestrained simulations at 298 K retain most of the native structures quite well except for a few flexible terminals and long internal loops. Starting from each homology model, a 150 ns MD simulation at 380 K generates the best RMSD improvement of 0.85 Å on average. The structural improvements roughly correlate with the RMSD of the initial homology models, indicating possible consistent structure refinement. Finally, targets TR614 and TR624 have been subjected to long-time replica-exchange MD simulations. Significant structural improvements are generated, with RMSD of 1.91 and 1.36 Å with respect to their crystal structures. Thus, it is possible to achieve realistic refinement of protein structure models to near-experimental accuracy, using accurate force field with sufficient conformational sampling.
全原子显式溶剂分子动力学（MD）模拟的一个重要应用是从低分辨率实验或基于模板的建模中优化蛋白质结构。一个关键要求是天然结构在力场下是稳定的。我们将最近开发的残基特异性力场RSFF1应用于最近CASP实验中的一组30个优化目标。从它们的实验结构开始，在298 K下进行1.0 μs的无约束模拟，除了一些柔性末端和长的内部环外，大部分天然结构保留得相当好。从每个同源模型开始，在380 K下进行150 ns的MD模拟，平均产生0.85 Å的最佳RMSD改善。结构改进大致与初始同源模型的RMSD相关，表明可能进行一致的结构优化。最后，对目标TR614和TR624进行了长时间的复制交换MD模拟。产生了显著的结构改进，相对于它们的晶体结构，RMSD分别为1.91 Å和1.36 Å。因此，使用精确的力场和足够的构象采样，可以将蛋白质结构模型优化到接近实验精度。
