Impact of distal mutations on the network of coupled motions correlated to hydride transfer in dihydrofolate reductase

Kim F. Wong, Tzvia Selzer, Stephen Benkovic, Sharon Hammes-Schiffer

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

A comprehensive analysis of the network of coupled motions correlated to hydride transfer in dihydrofolate reductase is presented. Hybrid quantum/classical molecular dynamics simulations are combined with a rank correlation analysis method to extract thermally averaged properties that vary along the collective reaction coordinate according to a prescribed target model. Coupled motions correlated to hydride transfer are identified throughout the enzyme. Calculations for wild-type dihydrofolate reductase and a triple mutant, along with the associated single and double mutants, indicate that each enzyme system samples a unique distribution of coupled motions correlated to hydride transfer. These coupled motions provide an explanation for the experimentally measured nonadditivity effects in the hydride transfer rates for these mutants. This analysis illustrates that mutations distal to the active site can introduce nonlocal structural perturbations and significantly impact the catalytic rate by altering the conformational motions of the entire enzyme and the probability of sampling conformations conducive to the catalyzed reaction.

Original languageEnglish (US)
Pages (from-to)6807-6812
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number19
DOIs
StatePublished - May 10 2005

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Tetrahydrofolate Dehydrogenase
Mutation
Enzymes
Molecular Dynamics Simulation
Catalytic Domain

All Science Journal Classification (ASJC) codes

  • General

Cite this

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abstract = "A comprehensive analysis of the network of coupled motions correlated to hydride transfer in dihydrofolate reductase is presented. Hybrid quantum/classical molecular dynamics simulations are combined with a rank correlation analysis method to extract thermally averaged properties that vary along the collective reaction coordinate according to a prescribed target model. Coupled motions correlated to hydride transfer are identified throughout the enzyme. Calculations for wild-type dihydrofolate reductase and a triple mutant, along with the associated single and double mutants, indicate that each enzyme system samples a unique distribution of coupled motions correlated to hydride transfer. These coupled motions provide an explanation for the experimentally measured nonadditivity effects in the hydride transfer rates for these mutants. This analysis illustrates that mutations distal to the active site can introduce nonlocal structural perturbations and significantly impact the catalytic rate by altering the conformational motions of the entire enzyme and the probability of sampling conformations conducive to the catalyzed reaction.",
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Impact of distal mutations on the network of coupled motions correlated to hydride transfer in dihydrofolate reductase. / Wong, Kim F.; Selzer, Tzvia; Benkovic, Stephen; Hammes-Schiffer, Sharon.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 19, 10.05.2005, p. 6807-6812.

Research output: Contribution to journalArticle

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T1 - Impact of distal mutations on the network of coupled motions correlated to hydride transfer in dihydrofolate reductase

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