Department of Chemical and Biomolecular Engineering, University of California Irvine, Irvine, California 92697, United States.
Department of Pharmaceutical Sciences, University of California Irvine, Irvine, California 92697, United States.
J Chem Theory Comput. 2024 Jul 23;20(14):6098-6110. doi: 10.1021/acs.jctc.4c00514. Epub 2024 Jul 8.
Alchemical free energy methods are useful in computer-aided drug design and computational protein design because they provide rigorous statistical mechanics-based estimates of free energy differences from molecular dynamics simulations. λ dynamics is a free energy method with the ability to characterize combinatorial chemical spaces spanning thousands of related systems within a single simulation, which gives it a distinct advantage over other alchemical free energy methods that are mostly limited to pairwise comparisons. Recently developed methods have improved the scalability of λ dynamics to perturbations at many sites; however, the size of chemical space that can be explored at each individual site has previously been limited to fewer than ten substituents. As the number of substituents increases, the volume of alchemical space corresponding to nonphysical alchemical intermediates grows exponentially relative to the size corresponding to the physical states of interest. Beyond nine substituents, λ dynamics simulations become lost in an alchemical morass of intermediate states. In this work, we introduce new biasing potentials that circumvent excessive sampling of intermediate states by favoring sampling of physical end points relative to alchemical intermediates. Additionally, we present a more scalable adaptive landscape flattening algorithm for these larger alchemical spaces. Finally, we show that this potential enables more efficient sampling in both protein and drug design test systems with up to 24 substituents per site, enabling, for the first time, simultaneous simulation of all 20 amino acids.
无化学计量自由能方法在计算机辅助药物设计和计算蛋白质设计中非常有用，因为它们提供了基于分子动力学模拟的严格统计力学自由能差异估计。λ动力学是一种自由能方法，能够在单个模拟中描述跨越数千个相关系统的组合化学空间，这使其与其他主要限于成对比较的无化学计量自由能方法相比具有明显优势。最近开发的方法提高了 λ动力学对许多位点扰动的可扩展性；然而，以前每个位点可以探索的化学空间大小限于少于十个取代基。随着取代基数量的增加，与物理状态对应的化学空间的体积相对于与非物理化学中间体对应的体积呈指数增长。超过九个取代基后，λ动力学模拟在中间状态的化学混乱中迷失。在这项工作中，我们引入了新的偏置势，通过相对于化学中间体优先采样物理终点来避免对中间状态的过度采样。此外，我们还为这些更大的化学空间提出了一种更具可扩展性的自适应景观平滑算法。最后，我们表明，这种势能够在具有每个位点多达 24 个取代基的蛋白质和药物设计测试系统中更有效地进行采样，从而首次能够同时模拟所有 20 种氨基酸。
