DOI: 10.1073/pnas.1230801100. Correlated motion and the effect of distal mutations in dihydrofolate reductase

10.1073/pnas.1230801100

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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.

Bibliography

Rod, T. H., Radkiewicz, J. L., & Brooks, C. L. (2003). Correlated motion and the effect of distal mutations in dihydrofolate reductase. Proceedings of the National Academy of Sciences, 100(12), 6980â6985.

Authors 3

Thomas H. Rod (first)
Jennifer L. Radkiewicz (additional)
Charles L. Brooks (additional)

References 27 Referenced 196

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Dates

Type	When
Created	22 years, 2 months ago (June 10, 2003, 1:06 p.m.)
Deposited	3 years, 3 months ago (April 25, 2022, 9:25 p.m.)
Indexed	3 months, 2 weeks ago (May 6, 2025, 1:08 p.m.)
Issued	22 years, 3 months ago (May 19, 2003)
Published	22 years, 3 months ago (May 19, 2003)
Published Online	22 years, 3 months ago (May 19, 2003)
Published Print	22 years, 2 months ago (June 10, 2003)

Funders 0

None

BibTeX

@article{Rod_2003, title={Correlated motion and the effect of distal mutations in dihydrofolate reductase}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.1230801100}, DOI={10.1073/pnas.1230801100}, number={12}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Rod, Thomas H. and Radkiewicz, Jennifer L. and Brooks, Charles L.}, year={2003}, month=may, pages={6980–6985} }

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  "abstract": "<jats:p>\n            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)\n            <jats:italic>Biochemistry</jats:italic>\n            41, 12618\u201312628]. On the basis of extensive  computer simulations for wild-type DHFR from\n            <jats:italic>Escherichia coli</jats:italic>\n            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.\n          </jats:p>",
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