Issue 37, 2010
From the journal:

Physical Chemistry Chemical Physics

Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase†

Natalia Kanaan,a   Maite Roca,b   Iñaki Tuñón,b   Sergio Martí*a  and  Vicent Moliner*ac  

* Corresponding authors

a Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castellón, Spain
E-mail: smarti@uji.es,, moliner@uji.es
Fax: (+34) 964-728066
Tel: (+34) 964-728071

b Departament de Química Física, Universitat de València, 46100 Burjassot, València, Spain

c Institute of Applied Radiation Chemistry, Technical University of Lodz, 90-924 Lodz, Poland

Abstract

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.

Graphical abstract: Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase

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Article information

DOI
https://doi.org/10.1039/C003799K
Article type
Paper
Submitted
02 Mar 2010
Accepted
16 Jun 2010
First published
16 Aug 2010

Phys. Chem. Chem. Phys., 2010,12, 11657-11664

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Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase

N. Kanaan, M. Roca, I. Tuñón, S. Martí and V. Moliner, Phys. Chem. Chem. Phys., 2010, 12, 11657 DOI: 10.1039/C003799K

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