Hydride transfer catalysed by Escherichia coli and Bacillus subtilis dihydrofolate reductase: Coupled motions and distal mutations

Sharon Hammes-Schiffer, James B. Watney

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


This paper reviews the results from hybrid quantum/classical molecular dynamics simulations of the hydride transfer reaction catalysed by wild-type (WT) and mutant Escherichia coli and WT Bacillus subtilis dihydrofolate reductase (DHFR). Nuclear quantum effects such as zero point energy and hydrogen tunnelling are significant in these reactions and substantially decrease the free energy barrier. The donor-acceptor distance decreases to ca 2.7 Å at transition-state configurations to enable the hydride transfer. A network of coupled motions representing conformational changes along the collective reaction coordinate facilitates the hydride transfer reaction by decreasing the donor-acceptor distance and providing a favourable geometric and electrostatic environment. Recent single-molecule experiments confirm that at least some of these thermally averaged equilibrium conformational changes occur on the millisecond time-scale of the hydride transfer. Distal mutations can lead to non-local structural changes and significantly impact the probability of sampling configurations conducive to the hydride transfer, thereby altering the free-energy barrier and the rate of hydride transfer. E. coli and B. subtilis DHFR enzymes, which have similar tertiary structures and hydride transfer rates with 44% sequence identity, exhibit both similarities and differences in the equilibrium motions and conformational changes correlated to hydride transfer, suggesting a balance of conservation and flexibility across species.

Original languageEnglish (US)
Pages (from-to)1365-1373
Number of pages9
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Issue number1472
StatePublished - Aug 29 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


  • Enzyme catalysis
  • Hydride transfer
  • Hydrogen tunnelling
  • Molecular dynamics


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