journal article

Journal Article

Text

Journal of Chemical Physics. 2023, 159(13), p. 134103

Elucidating protein-ligand binding kinetics based on returning probability theory

American Institute of Physics Inc.

English

Text

2023-10-07

https://doi.org/10.1063/5.0165692

Kasahara K., Masayama R., Okita K., et al. Elucidating protein-ligand binding kinetics based on returning probability theory. Journal of Chemical Physics 159, 134103 (2023); https://doi.org/10.1063/5.0165692.

The returning probability (RP) theory, a rigorous diffusion-influenced reaction theory, enables us to analyze the binding process systematically in terms of thermodynamics and kinetics using molecular dynamics (MD) simulations. Recently, the theory was extended to atomistically describe binding processes by adopting the host-guest interaction energy as the reaction coordinate. The binding rate constants can be estimated by computing the thermodynamic and kinetic properties of the reactive state existing in the binding processes. Here, we propose a methodology based on the RP theory in conjunction with the energy representation theory of solution, applicable to complex binding phenomena, such as protein-ligand binding. The derived scheme of calculating the equilibrium constant between the reactive and dissociate states, required in the RP theory, can be used for arbitrary types of reactive states. We apply the present method to the bindings of small fragment molecules [4-hydroxy-2-butanone (BUT) and methyl methylthiomethyl sulphoxide (DSS)] to FK506 binding protein (FKBP) in an aqueous solution. Estimated binding rate constants are consistent with those obtained from long-timescale MD simulations. Furthermore, by decomposing the rate constants to the thermodynamic and kinetic contributions, we clarify that the higher thermodynamic stability of the reactive state for DSS causes the faster binding kinetics compared with BUT.

This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in The Journal of Chemical Physics 159, 134103 (2023) and may be found at https://doi.org/10.1063/5.0165692.

93213

Elucidating protein-ligand binding kinetics based on returning probability theory

American Institute of Physics Inc.

English

2023-10-07

Journal of Chemical Physics

159

13

134103

https://doi.org/10.1063/5.0165692

https://hdl.handle.net/11094/93213