Accelerating the Calculation of Protein-Ligand Binding Free Energy and Residence Times Using Dynamically Optimized Collective Variables
Accelerating the Calculation of Protein-Ligand Binding Free Energy and Residence Times Using Dynamically Optimized Collective Variables
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DOI：
10.1021/acs.jctc.8b00934
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发表时间：
2019-01-01
影响因子：
5.5
通讯作者：
Parrinello, Michele
中科院分区：
文献类型：
--
作者：
Brotzakis, Z. Faidon;Limongelli, Vittorio;Parrinello, Michele
阐明配体/蛋白质结合相互作用在药理学中对于提高药物设计的成功率具有重要意义。为此，已经提出了许多计算方法，但是所有这些方法都受到限制，因为配体结合/不结合到分子靶标的过渡涉及许多缓慢的自由度，这妨碍了结合过程的全面表征。能够以简单和一般缓慢的自由度来表达这种转变将具有独特的优势，因为它将需要对所研究的系统的最低限度的了解，而反过来，它将阐明其物理学并加快依赖于集体变量的增强采样方法的收敛速度。在这项研究中，我们追求这一目标的第一次结合变分方法与漏斗metadaptics构象动力学。在这样做，我们预测的苯甲脒/胰蛋白酶系统的配体结合模式，我们准确地计算绝对蛋白质配体结合自由能和unbinding率在前所未有的低计算成本。最后，我们的模拟协议揭示了配体结合机制的能量和结构细节，并表明水和结合口袋溶剂化/去溶剂化是占主导地位的慢自由度。
Elucidation of the ligand/protein binding interaction is of paramount relevance in pharmacology to increase the success rate of drug design. To this end, a number of computational methods have been proposed; however all of them suffer from limitations since the ligand binding/unbinding transitions to the molecular target involve many slow degrees of freedom that hamper a full characterization of the binding process. Being able to express this transition in simple and general slow degrees of freedom would give a distinctive advantage, since it would require minimal knowledge of the system under study, while in turn it would elucidate its physics and accelerate the convergence speed of enhanced sampling methods relying on collective variables. In this study we pursuit this goal by combining for the first time variational approach to conformational dynamics with funnel metadynamics. In so doing, we predict for the benzamidine/trypsin system the ligand binding mode, and we accurately compute the absolute protein ligand binding free energy and unbinding rate at unprecedented low computational cost. Finally, our simulation protocol reveals the energetics and structural details of the ligand binding mechanism and shows that water and binding pocket solvation/desolvation are the dominant slow degrees of freedom.