Role of Repeated Conformational Transitions in Substrate Binding of Adenylate Kinase

Overview

Journal J Phys Chem B

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Oct 12

PMID 36222098

Authors

Jiajun Lu

David Scheerer

Gilad Haran

Wenfei Li

Wei Wang

Affiliations

Soon will be listed here.

Abstract

The catalytic cycle of the enzyme adenylate kinase involves large conformational motions between open and closed states. A previous single-molecule experiment showed that substrate binding tends to accelerate both the opening and the closing rates and that a single turnover event often involves multiple rounds of conformational switching. In this work, we showed that the repeated conformational transitions of adenylate kinase are essential for the relaxation of incorrectly bound substrates into the catalytically competent conformation by combining all-atom and coarse-grained molecular simulations. In addition, free energy calculations based on all-atom and coarse-grained models demonstrated that the enzyme with incorrectly bound substrates has much a lower free energy barrier for domain opening compared to that with the correct substrate conformation, which may explain the the acceleration of the domain opening rate by substrate binding. The results of this work provide mechanistic understanding to previous experimental observations and shed light onto the interplay between conformational dynamics and enzyme catalysis.

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