Department of Chemistry and Physical Sciences, Pace University, New York, New York 10038, United States.
Department of Science, Borough of Manhattan Community College, The City University of New York, New York, New York 10007, United States.
J Chem Theory Comput. 2020 Apr 14;16(4):2803-2813. doi: 10.1021/acs.jctc.9b01119. Epub 2020 Mar 9.
We present a new approach to more accurately and efficiently compute the absolute binding free energy for receptor-ligand complexes. Currently, the double decoupling method (DDM) and the potential of mean force method (PMF) are widely used to compute the absolute binding free energy of biomolecular complexes. DDM relies on alchemically decoupling the ligand from its environments, which can be computationally challenging for large ligands and charged ligands because of the large magnitude of the decoupling free energies involved. In contrast, the PMF method uses a physical pathway to directly transfer the ligand from solution to the receptor binding pocket and thus avoids some of the aforementioned problems in DDM. However, the PMF method has its own drawbacks: because of its reliance on a ligand binding/unbinding pathway that is free of steric obstructions from the receptor atoms, the method has difficulty treating ligands with buried atoms. To overcome the limitation in the standard PMF approach and enable buried ligands to be treated, here we develop a new method called AlchemPMF in which steric obstructions along the physical pathway for binding are alchemically removed. We have tested the new approach on two important drug targets involving charged ligands. One is HIV-1 integrase bound to an allosteric inhibitor; the other is the human telomeric DNA G-quadruplex in complex with a natural product protoberberine buried in the binding pocket. For both systems, the new approach leads to more reliable estimates of absolute binding free energies with smaller error bars and closer agreements with experiments compared with those obtained from the existing methods, demonstrating the effectiveness of the new method in overcoming the hysteresis often encountered in PMF binding free energy calculations of such systems. The new approach could also be used to improve the sampling of water equilibration and resolvation of the binding pocket as the ligand is extracted.
我们提出了一种新方法，可以更准确、更有效地计算受体-配体复合物的绝对结合自由能。目前，双去耦方法（DDM）和平均力势方法（PMF）被广泛用于计算生物分子复合物的绝对结合自由能。DDM 依赖于通过化学方法将配体与其环境去耦，对于大配体和带电配体来说，由于涉及的去耦自由能很大，因此计算上具有挑战性。相比之下，PMF 方法使用物理途径直接将配体从溶液转移到受体结合口袋，从而避免了 DDM 中上述一些问题。然而，PMF 方法也有其自身的缺点：由于它依赖于一条无受体原子空间位阻的配体结合/解吸途径，因此该方法难以处理埋藏原子的配体。为了克服标准 PMF 方法的局限性并使埋藏的配体能够被处理，我们在这里开发了一种新方法，称为 AlchemPMF，其中沿结合的物理途径的空间位阻通过化学方法被去除。我们已经在两个涉及带电配体的重要药物靶标上测试了新方法。一个是与变构抑制剂结合的 HIV-1 整合酶；另一个是与人端粒 DNA G-四链体复合的天然产物原小檗碱，其埋藏在结合口袋中。对于这两个系统，与现有方法相比，新方法得到的绝对结合自由能估计更可靠，误差更小，与实验结果更吻合，证明了新方法在克服此类系统的 PMF 结合自由能计算中经常遇到的滞后现象的有效性。新方法还可以用于改善水平衡和结合口袋再水合的采样，因为配体被提取出来。
