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Simulations of remote mutants of dihydrofolate reductase reveal the nature of a network of residues coupled to hydride transfer
Author(s) -
Roston Daniel,
Kohen Am,
Doron Dvir,
Major Dan T.
Publication year - 2014
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.23629
Subject(s) - dihydrofolate reductase , molecular mechanics , molecular dynamics , reaction coordinate , hamiltonian (control theory) , chemical physics , active site , chemistry , hydride , physics , kinetic energy , computational chemistry , catalysis , enzyme , quantum mechanics , biochemistry , hydrogen , mathematical optimization , mathematics
Recent experimental and theoretical studies have proposed that enzymes involve networks of coupled residues throughout the protein that participate in motions accompanying chemical barrier crossing. Here, we have examined portions of a proposed network in dihydrofolate reductase (DHFR) using quantum mechanics/molecular mechanics simulations. The simulations use a hybrid quantum mechanics‐molecular mechanics approach with a recently developed semiempirical AM1‐SRP Hamiltonian that provides accurate results for this reaction. The simulations reproduce experimentally determined catalytic rates for the wild type and distant mutants of E. coli DHFR, underscoring the accuracy of the simulation protocol. Additionally, the simulations provide detailed insight into how residues remote from the active site affect the catalyzed chemistry, through changes in the thermally averaged properties along the reaction coordinate. The mutations do not greatly affect the structure of the transition state near the bond activation, but we observe differences somewhat removed from the point of CH cleavage that affect the rate. The mutations have global effects on the thermally averaged structure that propagate throughout the enzyme and the current simulations highlight several interactions that appear to be particularly important. © 2014 Wiley Periodicals, Inc.