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Title: Reconciling Conformational Heterogeneity and Substrate Recognition in Cytochrome P450
Authors: Dandekar, B.
Keywords: Điều hòa tính; không đồng nhất; hình dạng; Cytochrome P; cơ chất
Issue Date: 2021
Publisher: bioRxiv
Abstract: Cytochrome P450, the ubiquitous metalloenzyme involved in detoxification of foreign components, has remained one of the most popular systems for substrate-recognition process. However, despite being known for its high substrate specificity, the mechanistic basis of substrate-binding by archetypal system cytochrome P450cam has remained at odds with the contrasting reports of multiple diverse crystallographic structures of its substrate-free form. Here we address this issue by elucidating the probability of mutual dynamical transition to the other crystallographic pose of cytochrome P450cam and vice versa via unbiasedall-atom computer simulation. A robust Markov state model (MSM), constructed using adaptively sampled 84 microsecond-longMolecular dynamics simulation trajectories, maps the broad and heterogenous P450cam conformational landscape into five keysub-states. In particular, the MSM identifies an intermediate-assisted dynamic equilibrium between a pair ofconformations ofP450cam, in which the substrate-recognition sites remain ‘closed’ and ‘open’ respectively. However, the estimate of a significantly high stationary population of closed conformation, coupled with faster rate of open ! closed transition than its reverse process,dictates that the net conformational equilibrium would be swayed in favour of ‘closed’ conformation. Together, the investigationquantitatively infers that while a potential substrate of cytochrome P450cam would in principle explore a diverse array ofconformations of substrate-free protein, it would mostly encounter a ‘closed’ or solvent-occluded conformation and hence wouldfollow an induced-fit based recognition process. Overall, the work reconciles multiple precedent crystallographic, spectroscopicinvestigations and establishes how a statistical elucidation of conformational heterogeneity in protein would provide crucialinsights in the mechanism of potential substrate-recognition process
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