Importance of base-pair opening for mismatch recognition

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Authors

BOUCHAL Tomáš DURNÍK Ivo ILLÍK Viktor RÉBLOVÁ Kamila KULHÁNEK Petr

Year of publication 2020
Type Article in Periodical
Magazine / Source Nucleic Acids Research
MU Faculty or unit

Faculty of Science

Citation
Web https://doi.org/10.1093/nar/gkaa896
Doi http://dx.doi.org/10.1093/nar/gkaa896
Keywords mismatch repair; MutS/DNA; adaptive biasing force; free energy; simple base-pair parameters
Description Mismatch repair is a highly conserved cellular pathway responsible for repairing mismatched dsDNA. Errors are detected by the MutS enzyme, which most likely senses altered mechanical property of damaged dsDNA rather than a specific molecular pattern. While the curved shape of dsDNA in crystallographic MutS/DNA structures suggests the role of DNA bending, the theoretical support is not fully convincing. Here, we present a computational study focused on a base-pair opening into the minor groove, a specific base-pair motion observed upon interaction with MutS. Propensities for the opening were evaluated in terms of two base-pair parameters: Opening and Shear. We tested all possible base pairs in anti/anti, anti/syn and syn/anti orientations and found clear discrimination between mismatches and canonical base-pairs only for the opening into the minor groove. Besides, the discrimination gap was also confirmed in hotspot and coldspot sequences, indicating that the opening could play a more significant role in the mismatch recognition than previously recognized. Our findings can be helpful for a better understanding of sequence-dependent mutability. Further, detailed structural characterization of mismatches can serve for designing anti-cancer drugs targeting mismatched base pairs.
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