Hydride transfer catalysed by Escherichia coli and Bacillus subtilis dihydrofolate reductase: coupled motions and distal mutations. Export

@article{citeulike:1005919, abstract = {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 A 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.}, address = {Department of Chemistry, Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802, USA. shs@chem.psu.edu}, author = {Hammes-Schiffer, S. and Watney, J. B.}, citeulike-article-id = {1005919}, citeulike-linkout-0 = {http://dx.doi.org/10.1098/rstb.2006.1869}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16873124}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16873124}, day = {29}, doi = {10.1098/rstb.2006.1869}, issn = {0962-8436}, journal = {Philos Trans R Soc Lond B Biol Sci}, keywords = {binding, catalysis, chemistry, dhfr, enzyme, kinetics, ligands, mutations, qmm, review, simulation}, month = {August}, number = {1472}, pages = {1365--1373}, posted-at = {2006-12-21 14:27:31}, priority = {2}, title = {Hydride transfer catalysed by Escherichia coli and Bacillus subtilis dihydrofolate reductase: coupled motions and distal mutations.}, url = {http://dx.doi.org/10.1098/rstb.2006.1869}, volume = {361}, year = {2006} }

TY - JOUR ID - citeulike:1005919 L3 - citeulike-article-id:1005919 N2 - 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 A 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. IS - 1472 JF - Philos Trans R Soc Lond B Biol Sci SN - 0962-8436 AD - Department of Chemistry, Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802, USA. shs@chem.psu.edu EP - 1373 TI - Hydride transfer catalysed by Escherichia coli and Bacillus subtilis dihydrofolate reductase: coupled motions and distal mutations. VL - 361 SP - 1365 KW - binding KW - catalysis KW - chemistry KW - dhfr KW - enzyme KW - kinetics KW - ligands KW - mutations KW - qmm KW - review KW - simulation AU - Hammes-Schiffer, S AU - Watney, JB PY - 2006/08/29/ UR - http://dx.doi.org/10.1098/rstb.2006.1869 ER -