Öhlknecht Christoph, Perthold Jan Walther, Lier Bettina, Oostenbrink Chris
Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna 1190, Austria.
J Chem Theory Comput. 2020 Dec 8;16(12):7721-7734. doi: 10.1021/acs.jctc.0c00719. Epub 2020 Nov 2.
Currently, two different methods dominate the field of biomolecular free-energy calculations for the prediction of binding affinities. Pathway methods are frequently used for large ligands that bind on the surface of a host, such as protein-protein complexes. Alchemical methods, on the other hand, are preferably applied for small ligands that bind to deeply buried binding sites. The latter methods are also widely known to be heavily artifacted by the representation of electrostatic energies in periodic simulation boxes, in particular, when net-charge changes are involved. Different methods have been described to deal with these artifacts, including postsimulation correction schemes and instantaneous correction schemes (e.g., co-alchemical perturbation of ions). Here, we use very simple test systems to show that instantaneous correction schemes with no change in the system net charge lower the artifacts but do not eliminate them. Furthermore, we show that free energies from pathway methods suffer from the same artifacts.
目前，在用于预测结合亲和力的生物分子自由能计算领域，有两种不同的方法占据主导地位。路径方法常用于结合在宿主表面的大配体，如蛋白质 - 蛋白质复合物。另一方面，炼金术方法则更适用于结合到深埋结合位点的小配体。众所周知，后一种方法在周期性模拟盒中静电能的表示方面存在严重的人为因素，特别是当涉及净电荷变化时。已经描述了不同的方法来处理这些人为因素，包括模拟后校正方案和瞬时校正方案（例如，离子的共炼金术扰动）。在这里，我们使用非常简单的测试系统来表明，系统净电荷不变的瞬时校正方案可降低人为因素，但不能消除它们。此外，我们表明路径方法的自由能也存在同样的人为因素。
