PMID:12756296
| Citation |
Rod, TH, Radkiewicz, JL and Brooks, CL 3rd (2003) Correlated motion and the effect of distal mutations in dihydrofolate reductase. Proc. Natl. Acad. Sci. U.S.A. 100:6980-5 |
|---|---|
| Abstract |
Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate. The catalytic rate in this system has been found to be significantly affected by mutations far from the site of chemical activity in the enzyme [Rajagopalan, P. T. R, Lutz, S., and Benkovic, S. J. (2002) Biochemistry 41, 12618-12628]. On the basis of extensive computer simulations for wild-type DHFR from Escherichia coli and four mutants (G121S, G121V, M42F, and M42F/G121S), we show that key parameters for catalysis are changed. The parameters we study are relative populations of different conformations sampled and hydrogen bonds. We find that the mutations result in long-range structural perturbations, rationalizing the effects that the mutations have on the kinetics of the enzyme. Such perturbations also provide a rationalization for the reported nonadditivity effect for double mutations. We finally examine the role a structural perturbation will have on the hydride transfer step. On the basis of our new findings, we discuss the role of coupled motions between distant regions in the enzyme, which previously was reported by Radkiewicz and Brooks. |
| Links |
PubMed PMC165816 Online version:10.1073/pnas.1230801100 |
| Keywords |
Computer Simulation; Escherichia coli/enzymology; Escherichia coli/genetics; Hydrogen Bonding; Kinetics; Models, Molecular; Motion; Mutagenesis, Site-Directed; Mutation; Protein Conformation; Tetrahydrofolate Dehydrogenase/chemistry; Tetrahydrofolate Dehydrogenase/genetics; Tetrahydrofolate Dehydrogenase/metabolism; Thermodynamics |
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