Institute for Biophysical Chemistry, Fritz-Hartmann-Centre for Medical Research, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Department of Chemistry and Biochemistry, Department of Physics, University of California, Santa Barbara, California 93106, USA.
J Chem Phys. 2021 Sep 14;155(10):104114. doi: 10.1063/5.0063664.
In this paper, we present a fast and adaptive correlation guided enhanced sampling method (CORE-MD II). The CORE-MD II technique relies, in part, on partitioning of the entire pathway into short trajectories that we refer to as instances. The sampling within each instance is accelerated by adaptive path-dependent metadynamics simulations. The second part of this approach involves kinetic Monte Carlo (kMC) sampling between the different states that have been accessed during each instance. Through the combination of the partition of the total simulation into short non-equilibrium simulations and the kMC sampling, the CORE-MD II method is capable of sampling protein folding without any a priori definitions of reaction pathways and additional parameters. In the validation simulations, we applied the CORE-MD II on the dialanine peptide and the folding of two peptides: TrpCage and TrpZip2. In a comparison with long time equilibrium Molecular Dynamics (MD), 1 µs replica exchange MD (REMD), and CORE-MD I simulations, we find that the level of convergence of the CORE-MD II method is improved by a factor of 8.8, while the CORE-MD II method reaches acceleration factors of ∼120. In the CORE-MD II simulation of TrpZip2, we observe the formation of the native state in contrast to the REMD and the CORE-MD I simulations. The method is broadly applicable for MD simulations and is not restricted to simulations of protein folding or even biomolecules but also applicable to simulations of protein aggregation, protein signaling, or even materials science simulations.
在本文中，我们提出了一种快速自适应相关引导增强采样方法（CORE-MD II）。CORE-MD II 技术部分依赖于将整个路径划分为我们称为实例的短轨迹。通过自适应路径相关元动力学模拟，加速每个实例内的采样。该方法的第二部分涉及在每个实例中访问的不同状态之间进行的动力学蒙特卡罗 (kMC) 采样。通过将总模拟划分为短非平衡模拟和 kMC 采样的组合，CORE-MD II 方法能够在没有任何关于反应途径和附加参数的先验定义的情况下对蛋白质折叠进行采样。在验证模拟中，我们将 CORE-MD II 应用于二丙氨酸肽和两种肽的折叠：TrpCage 和 TrpZip2。与长时间平衡分子动力学 (MD)、1µs 副本交换 MD (REMD) 和 CORE-MD I 模拟相比，我们发现 CORE-MD II 方法的收敛水平提高了 8.8 倍，而 CORE-MD II 方法达到的加速因子约为 120。在 TrpZip2 的 CORE-MD II 模拟中，我们观察到与 REMD 和 CORE-MD I 模拟相反的天然状态的形成。该方法广泛适用于 MD 模拟，不仅限于蛋白质折叠甚至生物分子的模拟，还适用于蛋白质聚集、蛋白质信号转导甚至材料科学模拟的模拟。
