Classical density functional theory (DFT) can be used to relate the thermodynamic properties of solutions to the indirect solvent mediated part of the solute–solvent potential of mean force (PMF). Standard, but powerful numerical methods can be used to estimate the solute–solvent PMF from which the indirect part can be extracted. In this work we show how knowledge of the direct and indirect parts of the solute–solvent PMF for water at the interface of a protein receptor can be used to gain insights about how to design tighter binding ligands. As we show, the indirect part of the solute–solvent PMF is equal to the sum of the 1-body (energy + entropy) terms in the inhomogeneous solvation theory (IST) expansion of the solvation free energy. To illustrate the effect of displacing interfacial water molecules with particular direct/indirect PMF signatures on the binding of ligands, we carry out simulations of protein binding with several pairs of congeneric ligands. We show that interfacial water locations that contribute favorably or unfavorably at the 1-body level (energy + entropy) to the solvation free energy of the solute can be targeted as part of the ligand design process. Water locations where the indirect PMF is larger in magnitude provide better targets for displacement when adding a functional group to a ligand core.

中文翻译：

---

界面水在蛋白质-配体结合中的作用：间接溶剂介导的平均力潜能

经典密度泛函理论（DFT）可用于将溶液的热力学性质与平均力（PMF）的溶质-溶剂势的间接溶剂介导部分联系起来。可使用标准但功能强大的数值方法来估计可从中提取出间接部分的溶质-溶剂PMF。在这项工作中，我们展示了如何利用蛋白质受体界面上水的溶质-溶剂PMF的直接和间接部分的知识来获得有关如何设计更紧密结合配体的见识。如我们所示，溶质-溶剂PMF的间接部分等于溶剂化自由能的非均质溶剂化理论（IST）扩展中的1体（能量+熵）项之和。为了说明用特定的直接/间接PMF标记置换界面水分子对配体结合的影响，我们对几对同类配体的蛋白质结合进行了模拟。我们显示出界面水位置有利地发挥了作用或在不利于溶质的溶剂化自由能的1体水平（能量+熵）的不利条件下，可以将其作为配体设计过程的一部分。当在配体核心中添加官能团时，间接PMF值较大的水位置提供了更好的置换目标。