Zhang Tong, Nguyen Phuong H, Nasica-Labouze Jessica, Mu Yuguang, Derreumaux Philippe
†Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Université Denis Diderot, Sorbonne Paris Cité, IBPC, 13 rue Pierre et Marie Curie, 75005 Paris, France.
‡School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
J Phys Chem B. 2015 Jun 11;119(23):6941-51. doi: 10.1021/acs.jpcb.5b03381. Epub 2015 May 29.
Following a previous report on a coarse-grained protein model in implicit solvent, we applied simulated tempering (ST) with on-the-fly Helmholtz free energy (weight factors) determination to the folding or aggregation of seven proteins with the CHARMM, OPLS, and AMBER protein, and the SPC and TIP3P water force fields. For efficiency and reliability, we also performed replica exchange molecular dynamics (REMD) simulations on the alanine di- and deca-peptide, and the dimer of the Aβ16-22 Alzheimer's fragment, and used experimental data and previous simulation results on the chignolin, beta3s, Trp-cage, and WW domain peptides of 10-37 amino acids. The sampling with ST is found to be more efficient than with REMD for a much lower CPU cost. Starting from unfolded or extended conformations, the WW domain and the Trp-cage peptide fold to their NMR structures with a backbone RMSD of 2.0 and 1 Å. Remarkably, the ST simulation explores transient non-native topologies for Trp-cage that have been rarely discussed by other simulations. Our ST simulations also show that the CHARMM22* force field has limitations in describing accurately the beta3s peptide. Taken together, these results open the door to the study of the configurations of single proteins, protein aggregates, and any molecular systems at atomic details in explicit solvent using a single normal CPU. They also demonstrate that our ST scheme can be used with any force field ranging from quantum mechanics to coarse-grain and atomistic.
继之前一篇关于隐式溶剂中粗粒度蛋白质模型的报告之后，我们将带有实时亥姆霍兹自由能（权重因子）测定的模拟回火（ST）应用于七种蛋白质的折叠或聚集研究，这些蛋白质使用了CHARMM、OPLS和AMBER蛋白质力场以及SPC和TIP3P水的力场。为了提高效率和可靠性，我们还对丙氨酸二肽和十肽以及Aβ16 - 22阿尔茨海默氏症片段的二聚体进行了副本交换分子动力学（REMD）模拟，并使用了关于10 - 37个氨基酸的chignolin、beta3s、色氨酸笼和WW结构域肽的实验数据及先前的模拟结果。结果发现，对于低得多的CPU成本，ST采样比REMD更有效。从未折叠或伸展构象开始，WW结构域和色氨酸笼肽折叠成它们的NMR结构，主链均方根偏差分别为2.0 Å和1 Å。值得注意的是，ST模拟探索了色氨酸笼的瞬态非天然拓扑结构，而其他模拟很少讨论这些结构。我们的ST模拟还表明，CHARMM22*力场在准确描述beta3s肽方面存在局限性。综上所述，这些结果为使用单个普通CPU在显式溶剂中以原子细节研究单个蛋白质、蛋白质聚集体及任何分子系统的构型打开了大门。它们还证明了我们的ST方案可与从量子力学到粗粒度和原子级的任何力场一起使用。
