Effect of mutation on enzyme motion in dihydrofolate reductase

James B. Watney, Pratul K. Agarwal, Sharon Hammes-Schiffer

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Hybrid quantum-classical molecular dynamics simulations of a mutant Escherichia coli dihydrofolate reductase enzyme are presented. Although residue 121 is on the exterior of the enzyme, experimental studies have shown that the mutation of Gly-121 to valine reduces the rate of hydride transfer by a factor of 163. The simulations indicate that the decrease in the hydride transfer rate for the G121V mutant is due to an increase in the free energy barrier. The calculated free energy barrier is higher for the mutant than for the wild-type enzyme by an amount that is consistent with the experimentally observed rate reduction. The calculated transmission coefficients are comparable for the wild-type and mutant enzymes. The simulations suggest that this mutation may interrupt a network of coupled promoting motions proposed to play an important role in DHFR catalysis. This phenomenon has broad implications for protein engineering and drug design.

Original languageEnglish (US)
Pages (from-to)3745-3750
Number of pages6
JournalJournal of the American Chemical Society
Volume125
Issue number13
DOIs
StatePublished - Apr 2 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint

Dive into the research topics of 'Effect of mutation on enzyme motion in dihydrofolate reductase'. Together they form a unique fingerprint.

Cite this