Theoretical Investigation of the role of water in hydrophobic key-lock association kinetics
Final Report Abstract
In this project, for the need of a better understanding of biomolecular recognition processes, we studied the possibility to create well-controlled solvent fluctuations in protein hydrophobic binding pockets to steer the ligand’s binding rates. We did this by means of a theoretical multi-scale approach of a generic key-lock systems in aqueous solution utilizing stochastic dynamical systems and molecular dynamics simulations. In particular, we rationalized the kinetic coupling of hydration fluctuations and ligand dynamics by means of the fluctuation-dissipation theorem. We explored the influence of the physicochemical properties of the pocket on local ligand diffusivities and binding rates, and demonstrated how the orientation of a (non-spherical) ligand couples to a pocket’s hydration fluctuations. We found that minor modulation in pocket depth can drastically speed up the binding rate and that, concurrently, binding to molded binding sites is advantageous for the rotational dynamics of the ligand. Throughout we elaborated on how the methods for key-lock binding kinetics add to our fundamental understanding of (bio)molecular processes far from equilibrium. The results and discussion of this work imply generic design principles for tailored solutions of functional host-guest systems as well as optimized drug’s in biomedical applications.
Publications
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Confined Water Determines Transport Properties of Guest Molecules in Narrow Pores. ACS Nano 10 (8), pp 7646–7656 (2016)
A. Phan, D. R. Cole, R. Gregor Weiß, J. Dzubiella and A. Striolo
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Solvent Fluctuations Induce Non-Markovian Kinetics in Hydrophobic Pocket-Ligand Binding. J. Phys. Chem. B, 120, 8127 (2016)
R. Gregor Weiß, Piotr Setny, Joachim Dzubiella
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Principles of tuning hydrophobic ligand-receptor binding kinetics. J. Chem. Theo. Comp. 13, 3012 (2017)
R. Gregor Weiß, Piotr. Setny, and Joachim Dzubiella
