Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase
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Otros documentos de la autoría: Kanaan Izquierdo, Natalia; Roca, Maite; Tuñón, Iñaki; Martí Forés, Sergio; Moliner, Vicent
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Título
Theoretical study of the temperature dependence of dynamic effects in thymidylate synthaseFecha de publicación
2010Editor
Royal Society of ChemistryISSN
1463-9076Cita bibliográfica
Physical Chemistry Chemical Physics (2010), 12, 37, p. 11657-11664Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
http://pubs.rsc.org/en/content/articlelanding/2010/cp/c003799kVersión
info:eu-repo/semantics/publishedVersionResumen
A theoretical study of the temperature dependence of dynamic effects in the rate limiting step of
the reaction catalyzed by thymidylate synthase is presented in this paper. From hybrid Quantum
Mechanics/Molecular ... [+]
A theoretical study of the temperature dependence of dynamic effects in the rate limiting step of
the reaction catalyzed by thymidylate synthase is presented in this paper. From hybrid Quantum
Mechanics/Molecular Mechanics (QM/MM) optimizations of transition state structures within a
fully flexible molecular model, free downhill molecular dynamics trajectories have been performed
at four different temperatures. The analysis of the reactive and non-reactive trajectories in the
enzyme environment has allowed us to study the geometric and electronic coupling between the
substrate, the cofactor and the protein. The results show how the contribution of dynamic effects
to the rate enhancement measured by the transmission coefficients is, at the four studied
temperatures, negligible. Nevertheless, the rare event trajectories performed have shown how the
hydride transfer and the scission of the conserved active site cysteine residue (Cys146 in E. coli)
take place in a concerted but asynchronous way; the latter takes place once the transfer has
occurred. The analysis of the dynamics of the protein reveals also how the relative movements of
some amino acids, especially Arg166, and a water molecule, promotes the departure of the
Cys146 from the dUMP. Finally, it seems that the protein environment creates an almost
invariant electric field in the active site of the protein that stabilizes the transition state of the
reaction, thus reducing the free energy barrier. [-]
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