On the Path to Optimal Alchemistry

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY The Protein Journal Pub Date : 2023-08-31 DOI:10.1007/s10930-023-10137-1
Magnus Lundborg, Jack Lidmar, Berk Hess
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Abstract

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.

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通往最佳炼金术之路
炼金术自由能的计算已成为一种标准和广泛使用的工具,特别是用于计算和比较药物的结合亲和力。虽然计算自由能的方法在过去的几十年里有了很大的改进,但在最终感兴趣的状态之间的路径选择通常仍然和20年前一样。我们将证明,这条路径的参数化基本上是任意的,隐式的选择。为了解决这个问题,需要使用路径长度或度量的概念。最近在加速权重直方图方法中引入的一个度量在这里也被证明是非常有用的。我们证明了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实际路径的选择。对于一组相关的用例,这些改进的组合可以将炼金术自由能计算的效率提高16倍。
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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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