Allosteric effects in cyclophilin mutants may be explained by changes in nano-microsecond time scale motions

Pattama Wapeesittipan, Antonia S.J.S. Mey, Malcolm D. Walkinshaw, Julien Michel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

This work investigates the connection between stochastic protein dynamics and function for the enzyme cyclophilin A (CypA) in wild-type form, and three variants that feature several mutations distal from the active site. Previous biophysical studies have suggested that conformational exchange between a ‘major’ active and a ‘minor’ inactive state on millisecond timescales plays a key role in catalysis for CypA. Here this hypothesis is addressed by a variety of molecular dynamics simulation techniques. Strikingly we show that exchange between major and minor active site conformations occurs at a rate that is 5 to 6 orders of magnitude faster than previously proposed. The minor active site conformation is found to be catalytically impaired, and decreased catalytic activity of the mutants is caused by changes in Phe113 motions on a ns-μs timescale. Therefore millisecond timescale motions may not be necessary to explain allosteric effects in cyclophilins.

Original languageEnglish
Article number41
Number of pages9
JournalCommunications Chemistry
Volume2
Early online date29 Mar 2019
DOIs
Publication statusPublished - 29 Mar 2019

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