利用非平衡候选蒙特卡罗法增强埋藏结合位点的水样采集。
Enhancing water sampling of buried binding sites using nonequilibrium candidate Monte Carlo.
机构信息
Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, USA.
出版信息
J Comput Aided Mol Des. 2021 Feb;35(2):167-177. doi: 10.1007/s10822-020-00344-8. Epub 2020 Sep 24.
Water molecules can be found interacting with the surface and within cavities in proteins. However, water exchange between bulk and buried hydration sites can be slow compared to simulation timescales, thus leading to the inefficient sampling of the locations of water. This can pose problems for free energy calculations for computer-aided drug design. Here, we apply a hybrid method that combines nonequilibrium candidate Monte Carlo (NCMC) simulations and molecular dynamics (MD) to enhance sampling of water in specific areas of a system, such as the binding site of a protein. Our approach uses NCMC to gradually remove interactions between a selected water molecule and its environment, then translates the water to a new region, before turning the interactions back on. This approach of gradual removal of interactions, followed by a move and then reintroduction of interactions, allows the environment to relax in response to the proposed water translation, improving acceptance of moves and thereby accelerating water exchange and sampling. We validate this approach on several test systems including the ligand-bound MUP-1 and HSP90 proteins with buried crystallographic waters removed. We show that our BLUES (NCMC/MD) method enhances water sampling relative to normal MD when applied to these systems. Thus, this approach provides a strategy to improve water sampling in molecular simulations which may be useful in practical applications in drug discovery and biomolecular design.
水分子可以与蛋白质的表面和空腔相互作用。然而,与模拟时间尺度相比,体相和埋藏水合位点之间的水交换可能较慢,从而导致对水的位置的采样效率低下。这可能会给计算机辅助药物设计的自由能计算带来问题。在这里,我们应用一种混合方法,将非平衡候选蒙特卡罗(NCMC)模拟和分子动力学(MD)相结合,以增强系统特定区域(如蛋白质结合位点)的水的采样。我们的方法使用 NCMC 逐渐去除选定水分子与其环境之间的相互作用,然后将水转移到新区域,然后重新打开相互作用。这种逐渐去除相互作用的方法,然后移动并重新引入相互作用,允许环境对所提出的水迁移做出响应,从而提高迁移的接受率,从而加速水交换和采样。我们在包括配体结合的 MUP-1 和 HSP90 蛋白在内的几个测试系统上验证了这种方法,这些蛋白中的埋藏晶体水已被去除。我们表明,当应用于这些系统时,我们的 BLUES(NCMC/MD)方法相对于正常 MD 提高了水的采样。因此,这种方法为提高分子模拟中的水采样提供了一种策略,这在药物发现和生物分子设计的实际应用中可能很有用。