Miao Yinglong, Feixas Ferran, Eun Changsun, McCammon J Andrew
Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California.
J Comput Chem. 2015 Jul 30;36(20):1536-49. doi: 10.1002/jcc.23964. Epub 2015 Jun 12.
Folding of four fast-folding proteins, including chignolin, Trp-cage, villin headpiece and WW domain, was simulated via accelerated molecular dynamics (aMD). In comparison with hundred-of-microsecond timescale conventional molecular dynamics (cMD) simulations performed on the Anton supercomputer, aMD captured complete folding of the four proteins in significantly shorter simulation time. The folded protein conformations were found within 0.2-2.1 Å of the native NMR or X-ray crystal structures. Free energy profiles calculated through improved reweighting of the aMD simulations using cumulant expansion to the second-order are in good agreement with those obtained from cMD simulations. This allows us to identify distinct conformational states (e.g., unfolded and intermediate) other than the native structure and the protein folding energy barriers. Detailed analysis of protein secondary structures and local key residue interactions provided important insights into the protein folding pathways. Furthermore, the selections of force fields and aMD simulation parameters are discussed in detail. Our work shows usefulness and accuracy of aMD in studying protein folding, providing basic references in using aMD in future protein-folding studies.
通过加速分子动力学（aMD）模拟了包括奇诺林、色氨酸笼、绒毛蛋白头部结构域和WW结构域在内的四种快速折叠蛋白的折叠过程。与在Anton超级计算机上进行的长达数百微秒时间尺度的传统分子动力学（cMD）模拟相比，aMD在显著更短的模拟时间内捕捉到了这四种蛋白的完全折叠。发现折叠后的蛋白构象与天然核磁共振（NMR）或X射线晶体结构相差0.2 - 2.1 Å。通过使用累积量展开到二阶对aMD模拟进行改进重加权计算得到的自由能分布与从cMD模拟获得的结果高度一致。这使我们能够识别除天然结构之外的不同构象状态（例如未折叠和中间状态）以及蛋白折叠能垒。对蛋白质二级结构和局部关键残基相互作用的详细分析为蛋白质折叠途径提供了重要见解。此外，还详细讨论了力场和aMD模拟参数的选择。我们的工作展示了aMD在研究蛋白质折叠方面的实用性和准确性，为未来蛋白质折叠研究中使用aMD提供了基础参考。
