Principles for Tuning Hydrophobic Ligand-Receptor Binding Kinetics.
Principles for Tuning Hydrophobic Ligand-Receptor Binding Kinetics.
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DOI：
10.1021/acs.jctc.7b00216
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发表时间：
2017-05
影响因子：
5.5
通讯作者：
R. G. Weiß;P. Setny;J. Dzubiella
中科院分区：
文献类型：
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作者：
R. G. Weiß;P. Setny;J. Dzubiella
我们研究了如何调整疏水配体-受体缔合的速率，由于溶剂的作用，在可调受体口袋的显式水分子动力学（MD）模拟。我们的模型认为结合的球形配体（钥匙/客人）的凹面凹陷的非极性壁受体（锁/主机）。我们系统地修改受体的物理化学性质的几何形状和分散的吸引力，这反过来又改变了口袋内的水的占用和波动。我们证明，即使是微小的口袋修改可以导致水介导的协会的显着加速。例如，如果绑定口袋仅稍微变深，则绑定从慢速切换到快速。我们发现，疏水性的程度，其特征在于由水合占有率和其波动，清楚地与结合时间，例如，链接的突然加速到疏水性的突然增加。为了更深入的分析，通过时间理论的基础上，我们量化的溶剂波动和配体的局部动力学和摩擦之间的密切耦合。偶联表现出实质性的非平衡效应，并在结合前不久最大化，这在所有情况下都减慢了结合动力学。总之，我们合理化的物理化学性质的非极性，凹结合位点调整键锁结合动力学由于水介导的力量和波动。因此，我们的研究补充了对溶剂在主客体结合中的影响的深刻理解，这对于催化和制药应用中的定制解决方案至关重要。
We investigate how to tune the rate of hydrophobic ligand-receptor association due to the role of solvent in adjustable receptor pockets by explicit-water molecular dynamics (MD) simulations. Our model considers the binding of a spherical ligand (key/guest) to a concave surface recess in a nonpolar wall as receptor (lock/host). We systematically modify the receptor's physicochemical properties in terms of geometry and dispersion attraction which, in turn, alter the water occupancy and fluctuations within the pocket. We demonstrate that even minor pocket modifications can lead to a significant acceleration of the water-mediated association. For example, the binding switches from comparably slow to fast if the binding pocket becomes only slightly deeper. We find that the degree of hydrophobicity, characterized by hydration occupancy and its fluctuations, clearly correlates with the binding times and, for instance, links the sudden acceleration to an abrupt increase in hydrophobicity. For a deeper analysis based on passage time theory, we quantify the intimate coupling between solvent fluctuations and the ligand's local dynamics and friction. The coupling exhibits substantial nonequilibrium effects and maximizes shortly before binding, which slows down the binding kinetics in all cases. In summary, we rationalize how the physicochemical properties of a nonpolar, concave binding site tune key-lock binding kinetics due to water-mediated forces and fluctuations. Our study thus complements the profound understanding of the solvent's influence in host-guest binding, which is essential for tailored solutions in catalysis and pharmaceutical applications.