Theoretical Chemistry, Ruhr University Bochum, D-44780 Bochum, Germany.
J Chem Theory Comput. 2020 Jul 14;16(7):4615-4630. doi: 10.1021/acs.jctc.9b01150. Epub 2020 Jun 22.
Enhanced sampling techniques are a promising approach to obtain reliable binding free-energy profiles for flexible protein-ligand complexes from molecular dynamics (MD) simulations. To put four popular enhanced sampling techniques to a biologically relevant and challenging test, we studied the partial dissociation of an antigenic peptide from the Major Histocompatibility Complex I (MHC I) HLA-B*35:01 to systematically investigate the performance of umbrella sampling (US), replica exchange with solute tempering 2 (REST2), bias exchange umbrella sampling (BEUS, or replica-exchange umbrella sampling), and well-tempered metadynamics (MTD). With regard to the speed of sampling and convergence, the peptide-MHC I complex (pMHC I) under study showcases intrinsic strengths and weaknesses of the four enhanced sampling techniques used. We found that BEUS can best handle the sampling challenges that arise from the coexistence of an enthalpically and an entropically stabilized free-energy minimum in the pMHC I under study. These findings might also be relevant for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.
增强采样技术是一种很有前途的方法，可以从分子动力学 (MD) 模拟中为柔性蛋白-配体复合物获得可靠的结合自由能曲线。为了对四种流行的增强采样技术进行具有生物学相关性和挑战性的测试，我们研究了抗原肽从主要组织相容性复合体 I (MHC I) HLA-B*35:01 的部分解离，以系统地研究了伞状采样 (US)、溶剂温度交换 2 (REST2) 的复制交换、偏置交换伞状采样 (BEUS，或复制交换伞状采样) 和调谐分子动力学 (MTD) 的性能。就采样速度和收敛性而言，所研究的肽-MHC I 复合物 (pMHC I) 展示了所使用的四种增强采样技术的固有优势和劣势。我们发现，BEUS 可以最好地处理在所研究的 pMHC I 中同时存在焓和熵稳定的自由能最小值所带来的采样挑战。这些发现对于其他具有竞争焓和熵稳定最小值的柔性生物分子系统也可能具有相关性。
