Principles for Tuning Hydrophobic Ligand–Receptor Binding Kinetics

Abstract

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.

Transfer Free Energies and Partitioning of Small Molecules in Collapsed PNIPAM Polymers

“…However, the entropy being so small in magnitude and independent of size is remarkable. We believe also that water molecules with non-saturated hydrogen bonds removed from hydrophobic cavities inside the polymer upon insertion contribute significantly to the free energy, in particular with favorable enthalpy and unfavorable entropy contributions [70,71]. This enthalpy-driven hydrophobic solvation can also be envisioned as a complementary association of apolar (concave) pocket-(convex) ligand binding, whose thermodynamic signature hardly depends on the particular pocket/ligand geometry [72].…”

Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38α MAP Kinase Type-I/II/III Inhibitors

“…The pocket-water fluctuations shown in our simulations are worth further investigation using passage time theory, density profile, or free energy landscape to reveal the transitions between locally wet and dry regions that may deepen our understanding on unbinding kinetics. 75–77 In addition, different water models may slightly influence protein and ligand dynamics, which may have an effect on modeling binding kinetics as well. 78 …”

Affinity, kinetics, and pathways of anisotropic ligands binding to hydrophobic model pockets

“…Thus, the peak height ∆ξ, position z p and width σ define a peak that adds to the bulk friction constant ξ ∞ . This peak roots from pocket hydration fluctuations as we also previously discussed for binding of a spherical ligand to the same pocket [24] which we replot here as gray circles. The key to the additional dissipative forces are the bimodal wet-dry hydration fluctuations which couple to the ligand.…”

“…The simulation setup is illustrated in Fig. 2 and 3 which is the same as in our previous study [24]. The ligand binding process is constrained to one-dimensional diffusion along z, the distance of the ligand center-of-mass perpendicular to the pocketed wall shown in To probe selected observables as functions of the ligand separation to the binding site we utilized umbrella sampling simulations along z.…”

“…Previously we discussed that the pocket water density fluctuations yield additional dissipative forces that slow the binding [19,24,36]. Firstly, pocket water occupancy fluctuations and ligand friction were shown to couple [19].…”