Mechanism of the Glycosidic Bond Cleavage of Mismatched Thymine in Human Thymine DNA Glycosylase Revealed by Classical Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations

Kanaan N, Crehuet R, Imhof P (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Journal of Physical Chemistry B American Chemical Society

Book Volume: 119

Pages Range: 12365-12380

Journal Issue: 38

DOI: 10.1021/acs.jpcb.5b05496

Abstract

Base excision of mismatched or damaged nucleotides catalyzed by glycosylase enzymes is the first step of the base excision repair system, a machinery preserving the integrity of DNA. Thymine DNA glycosylase recognizes and removes mismatched thymine by cleaving the C1′-N1 bond between the base and the sugar ring. Our quantum mechanical/molecular mechanical calculations of this reaction in human thymine DNA glycosylase reveal a requirement for a positive charge in the active site to facilitate C1′-N1 bond scission: protonation of His151 significantly lowers the free energy barrier for C1′-N1 bond dissociation compared to the situation with neutral His151. Shuttling a proton from His151 to the thymine base further reduces the activation free energy for glycosidic bond cleavage. Classical molecular dynamics simulations of the H151A mutant suggest that the mutation to the smaller, neutral, residue increases the water accessibility of the thymine base, rendering direct proton transfer from the bulk feasible. Quantum mechanical/molecular mechanical calculations of the glycosidic bond cleavage reaction in the H151A mutant show that the activation free energy is slightly lower than in the wild-type enzyme, explaining the experimentally observed higher reaction rates in this mutant.

Authors with CRIS profile

Petra Imhof

Involved external institutions

Freie Universität Berlin DE Germany (DE) Spanish National Research Council / Consejo Superior de Investigaciones Científicas (CSIC) ES Spain (ES)

How to cite

APA:

Kanaan, N., Crehuet, R., & Imhof, P. (2015). Mechanism of the Glycosidic Bond Cleavage of Mismatched Thymine in Human Thymine DNA Glycosylase Revealed by Classical Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations. Journal of Physical Chemistry B, 119(38), 12365-12380. https://dx.doi.org/10.1021/acs.jpcb.5b05496

MLA:

Kanaan, Natalia, Ramon Crehuet, and Petra Imhof. "Mechanism of the Glycosidic Bond Cleavage of Mismatched Thymine in Human Thymine DNA Glycosylase Revealed by Classical Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations." Journal of Physical Chemistry B 119.38 (2015): 12365-12380.

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