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Entropic and enthalpic contributions to stereospecific ligand binding from enhanced sampling methods.


ABSTRACT: The stereoselective binding of R- and S-propranolol to the metabolic enzyme cytochrome P450 2D6 and its mutant F483A was studied using various computational approaches. Previously reported free-energy differences from Hamiltonian replica exchange simulations, combined with thermodynamic integration, are compared to the one-step perturbation approach, combined with local-elevation enhanced sampling, and an excellent agreement between methods was obtained. Further, the free-energy differences are interpreted in terms of enthalpic and entropic contributions where it is shown that exactly compensating contributions obscure a molecular interpretation of differences in the affinity while various reduced terms allow a more detailed analysis, which agree with heuristic observations on the interactions.

SUBMITTER: Lai B 

PROVIDER: S-EPMC3904767 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other

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