PMID:12656604

Citation	Watney, JB, Agarwal, PK and Hammes-Schiffer, S (2003) Effect of mutation on enzyme motion in dihydrofolate reductase. J. Am. Chem. Soc. 125:3745-50
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.
Links	PubMed Online version:10.1021/ja028487u
Keywords	Amino Acid Substitution; Computer Simulation; Escherichia coli/enzymology; Glycine/chemistry; Glycine/genetics; Humans; Kinetics; Models, Chemical; Models, Molecular; Mutation; Protein Conformation; Quantum Theory; Tetrahydrofolate Dehydrogenase/chemistry; Tetrahydrofolate Dehydrogenase/genetics; Tetrahydrofolate Dehydrogenase/metabolism; Thermodynamics; Valine/chemistry; Valine/genetics
edit table

Significance

You can help EcoliWiki by summarizing why this paper is useful

Useful Materials and Methods

You can help Ecoliwiki by describing the useful materials (strains, plasmids, antibodies, etc) described in this paper.

Annotations

<annotationlinks/>

EcoliWiki Links

Add links to pages that link here (e.g. gene, product, method pages)

References

See Help:References for how to manage references in EcoliWiki.