Geometry-encoded molecular dynamics enables deep learning insights into P450 regiospecificity control.

ABSTRACT: Cytochrome P450 1A2, as many isoenzymes, can generate multiple metabolites from a single substrate. A loose coupling between substrate binding and oxygen activation makes possible substrate reorientations at the active site prior to catalysis. In the present work, caffeine oxidation to alternative bioactive compounds was used to decipher this pluripotency. A model involving two interacting subsites capable of sequentially accommodating one or two caffeine molecules was considered. Molecular dynamics was used to characterize subsite interactions and feed a dedicated geometric encoding of trajectories that was coupled to dimensional reductions and differential machine learning. The two subsites differentially control caffeine orientations and can exchange substrate through a phenylalanine ga

SUBMITTER: Pompon D 

PROVIDER: S-EPMC11876329 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature