Correlated motion and the effect of distal mutations in dihydrofolate reductase. Export

@article{citeulike:1005915, 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.}, address = {Department of Molecular Biology, The Scripps Research Institute, TPC6, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.}, author = {Rod, T. H. and Radkiewicz, J. L. and Brooks, C. L.}, citeulike-article-id = {1005915}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.1230801100}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/12756296}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=12756296}, day = {10}, doi = {10.1073/pnas.1230801100}, issn = {0027-8424}, journal = {Proc Natl Acad Sci U S A}, keywords = {binding, catalysis, chemistry, dhfr, enzyme, ligands, md, motion, mutations, protein, simulation}, month = {June}, number = {12}, pages = {6980--6985}, posted-at = {2006-12-21 14:20:49}, priority = {2}, title = {Correlated motion and the effect of distal mutations in dihydrofolate reductase.}, url = {http://dx.doi.org/10.1073/pnas.1230801100}, volume = {100}, year = {2003} }

TY - JOUR ID - citeulike:1005915 L3 - citeulike-article-id:1005915 N2 - 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. IS - 12 JF - Proc Natl Acad Sci U S A SN - 0027-8424 AD - Department of Molecular Biology, The Scripps Research Institute, TPC6, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. EP - 6985 TI - Correlated motion and the effect of distal mutations in dihydrofolate reductase. VL - 100 SP - 6980 KW - binding KW - catalysis KW - chemistry KW - dhfr KW - enzyme KW - ligands KW - md KW - motion KW - mutations KW - protein KW - simulation AU - Rod, TH AU - Radkiewicz, JL AU - Brooks, CL PY - 2003/06/10/ UR - http://dx.doi.org/10.1073/pnas.1230801100 ER -