Riccardi Enrico, Krämer Andreas, van Erp Titus S, Ghysels An
Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, 7491 Trondheim, Norway.
Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
J Phys Chem B. 2021 Jan 14;125(1):193-201. doi: 10.1021/acs.jpcb.0c09947. Epub 2020 Dec 28.
Several simulations strategies have emerged to predict the permeability of solutes across membranes, which is important for many biological or industrial processes such as drug design. The widespread inhomogeneous solubility-diffusion (ISD) model is based on the Smoluchowski equation and describes permeation as purely diffusive. The counting method, which counts membrane transitions in a long molecular dynamics (MD) trajectory, is free of this diffusive assumption, but it lacks sufficient statistics when the permeation involves high free energy barriers. Metadynamics and variations thereof can overcome such barriers, but they generally lack the kinetics information. The milestoning framework has been used to describe permeation as a rare event, but it still relies on the Markovian assumption between the milestones. Replica Exchange Transition Interface Sampling (RETIS) has been shown to be an effective method for sampling rare events while simultaneously describing the kinetics without assumptions. This paper is the first permeation application of RETIS on an all-atom lipid bilayer consisting of 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine (POPC) to compute the entrance, escape and complete transition of molecular oxygen. Conventional MD was performed as a benchmark, and the MD rates from counting were converted to rate constants, giving good agreement with the RETIS values. Moreover, a correction factor was derived to convert the collective order parameter in RETIS, which was aimed to improve efficiency, to a single-particle order parameter. With this work, we showed how the exact kinetics of drug molecules permeation can be assessed with RETIS even if the permeation is truly a rare event or if the permeation is non-Markovian. RETIS will therefore be a valuable tool for future permeation studies.
已经出现了几种模拟策略来预测溶质跨膜的渗透性，这对于许多生物或工业过程（如药物设计）都很重要。广泛使用的非均匀溶解度 - 扩散（ISD）模型基于斯莫卢霍夫斯基方程，将渗透描述为纯粹的扩散过程。计数方法通过统计长分子动力学（MD）轨迹中的膜跃迁来进行，它没有这种扩散假设，但当渗透涉及高自由能垒时，缺乏足够的统计数据。元动力学及其变体可以克服此类障碍，但它们通常缺乏动力学信息。里程碑框架已被用于将渗透描述为罕见事件，但它仍然依赖于里程碑之间的马尔可夫假设。副本交换过渡界面采样（RETIS）已被证明是一种有效方法，可用于对罕见事件进行采样，同时无需假设即可描述动力学。本文首次将RETIS应用于由1 - 棕榈酰 - 2 - 油酰 - sn - 甘油 - 3 - 磷酸胆碱（POPC）组成的全原子脂质双层，以计算分子氧的进入、逸出和完全跃迁。以传统分子动力学作为基准，将计数法得到的分子动力学速率转换为速率常数，与RETIS值吻合良好。此外，还推导了一个校正因子，将RETIS中的集体序参量转换为单粒子序参量，旨在提高效率。通过这项工作，我们展示了即使渗透是真正的罕见事件或非马尔可夫过程，也可以使用RETIS评估药物分子渗透的确切动力学。因此，RETIS将成为未来渗透研究的宝贵工具。
