2003
DOI: 10.1073/pnas.1230801100
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Correlated motion and the effect of distal mutations in dihydrofolate reductase

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 M42F͞ G121S), we show that key parameters for catalysis … Show more

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Cited by 215 publications
(313 citation statements)
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“…This might increase flexibility, making deformations easier to accommodate larger substrates, or couple thermal energy into the reaction pathway. 25,26 It is appropriate to consider the experimental thermal anisotropic measurements on which we base this argument. The magnitude of the anisotropic movement is evaluated using an anisotropy parameter that ranges from 0 to 1, with 1 indicating an ideally isotropic atom.…”
Section: Active Sitementioning
confidence: 99%
See 1 more Smart Citation
“…This might increase flexibility, making deformations easier to accommodate larger substrates, or couple thermal energy into the reaction pathway. 25,26 It is appropriate to consider the experimental thermal anisotropic measurements on which we base this argument. The magnitude of the anisotropic movement is evaluated using an anisotropy parameter that ranges from 0 to 1, with 1 indicating an ideally isotropic atom.…”
Section: Active Sitementioning
confidence: 99%
“…[21][22][23] Here, a coordinated motion aspect of the relationship, long hypothesized for enzymes, is apparent at ultrahigh resolution. 25,26 …”
Section: Activity and Stability Tradeoffmentioning
confidence: 99%
“…While it is difficult to unambiguously demonstrate whether collective dynamics involving a network of residues facilitates catalysis [17], it is clear that enzymes sample a number of distinct states during a reaction cycle. In the best studied example of E. coli dihydrofolate reductase (DHFR) the role of the conformational motions in the enzyme in facilitating the hydride transfer has been linked using mutational studies [10,18,19], NMR relaxation dispersion measurements [20,21,22] that probe the dynamics on µs to ms time scale, molecular dynamics simulations [6,7,13], and sequence analysis [6].…”
Section: Introductionmentioning
confidence: 99%
“…The most sophisticated computational approaches to protein dynamics, all-atom molecular dynamics simulations, rely on local additivity by employing two-body atom-atom interaction potentials. Nevertheless, despite the local additivity assumption, global nonadditivity and other nonlocal effects can be predicted (21). Furthermore, in virtually all statistical mechanical models that employ free energy decomposition schemes, additivity assumptions are not only applied to the potential energy (enthalpy) contributions, but also to entropy contributions.…”
Section: Introductionmentioning
confidence: 99%