Zhou Rui, Maisuradze Gia G, Suñol David, Todorovski Toni, Macias Maria J, Xiao Yi, Scheraga Harold A, Czaplewski Cezary, Liwo Adam
Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301; Biomolecular Physics and Modeling Group, Department of Physics, Huazhong University of Science and Technology, Wuhan 430074, China; Laboratory of Molecular Modeling, Faculty of Chemistry, University of Gdańsk, 80-308 Gdańsk, Poland;
Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853-1301;
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18243-8. doi: 10.1073/pnas.1420914111. Epub 2014 Dec 8.
To demonstrate the utility of the coarse-grained united-residue (UNRES) force field to compare experimental and computed kinetic data for folding proteins, we have performed long-time millisecond-timescale canonical Langevin molecular dynamics simulations of the triple β-strand from the Formin binding protein 28 WW domain and six nonnatural variants, using UNRES. The results have been compared with available experimental data in both a qualitative and a quantitative manner. Complexities of the folding pathways, which cannot be determined experimentally, were revealed. The folding mechanisms obtained from the simulated folding kinetics are in agreement with experimental results, with a few discrepancies for which we have accounted. The origins of single- and double-exponential kinetics and their correlations with two- and three-state folding scenarios are shown to be related to the relative barrier heights between the various states. The rate constants obtained from time profiles of the fractions of the native, intermediate, and unfolded structures, and the kinetic equations fitted to them, correlate with the experimental values; however, they are about three orders of magnitude larger than the experimental ones for most of the systems. These differences are in agreement with the timescale extension derived by scaling down the friction of water and averaging out the fast degrees of freedom when passing from all-atom to a coarse-grained representation. Our results indicate that the UNRES force field can provide accurate predictions of folding kinetics of these WW domains, often used as models for the study of the mechanisms of proein folding.
为了证明粗粒度联合残基（UNRES）力场在比较折叠蛋白的实验动力学数据和计算动力学数据方面的效用，我们使用UNRES对Formin结合蛋白28 WW结构域的三股β链和六个非天然变体进行了长时间的毫秒级正则朗之万分子动力学模拟。已将结果与现有实验数据进行了定性和定量比较。揭示了无法通过实验确定的折叠途径的复杂性。从模拟折叠动力学获得的折叠机制与实验结果一致，不过存在一些差异，我们对此进行了解释。单指数和双指数动力学的起源及其与两态和三态折叠情况的相关性表明与不同状态之间的相对势垒高度有关。从天然、中间和未折叠结构分数的时间分布获得的速率常数以及拟合它们的动力学方程与实验值相关；然而，对于大多数系统，它们比实验值大约大三个数量级。这些差异与通过降低水的摩擦力并在从全原子表示过渡到粗粒度表示时平均掉快速自由度而得出的时间尺度扩展一致。我们的结果表明，UNRES力场可以为这些WW结构域的折叠动力学提供准确预测，这些结构域常被用作研究蛋白质折叠机制的模型。
