Alchemical free energy calculations have become a standard and widely used tool, in particular for calculating and comparing binding affinities of drugs. Although methods to compute such free energies have improved significantly over the last decades, the choice of path between the end states of interest is usually still the same as two decades ago. We will show that there is a fundamentally arbitrary, implicit choice of parametrization of this path. To address this, the notion of the length of a path or a metric is required. A metric recently introduced in the context of the accelerated weight histogram method also proves to be very useful here. We demonstrate that this metric can not only improve the efficiency of sampling along a given path, but that it can also be used to improve the actual choice of path. For a set of relevant use cases, the combination of these improvements can increase the efficiency of alchemical free energy calculations by up to a factor 16.

炼金术自由能计算已成为一种标准且广泛使用的工具，特别是用于计算和比较药物的结合亲和力。尽管计算此类自由能的方法在过去几十年中得到了显着改进，但感兴趣的最终状态之间的路径选择通常仍然与二十年前相同。我们将证明这条路径的参数化基本上是任意的、隐含的选择。为了解决这个问题，需要路径长度或度量的概念。最近在加速权重直方图方法的背景下引入的度量也被证明在这里非常有用。我们证明该度量不仅可以提高沿给定路径的采样效率，而且还可以用于改进路径的实际选择。对于一组相关用例，这些改进的结合可以将炼金自由能计算的效率提高多达 16 倍。