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.

可以发现水分子与蛋白质表面和空腔内相互作用。然而，与模拟时间尺度相比，大量和埋藏水化地点之间的水交换可能很慢，从而导致水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（例如蛋白质的结合位点）的水采样。我们的方法使用 NCMC 逐渐消除选定的水分子与其环境之间的相互作用，然后将水转移到新的区域，然后重新打开相互作用。这种逐渐消除相互作用，然后移动然后重新引入相互作用的方法，允许环境放松以响应拟议的水转移，提高对移动的接受度，从而加速水交换和采样。我们在多个测试系统上验证了这种方法，包括去除了埋藏结晶水的配体结合的 MUP-1 和 HSP90 蛋白。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 增强了水采样。因此，这种方法提供了一种改进分子模拟中水采样的策略，这可能在药物发现和生物分子设计的实际应用中有用。