Thermodynamic stabilities of base pairs composed of 36 unique combinations of A, G, T, and C nucleobases in both anti and syn conformations in the central part of 13-nt long palindromic DNA were characterized by biased molecular dynamics simulations. The bias was introduced through two base pair parameters, opening and shear, which cover all possible arrangements of nucleobases in the base pair plane. In total, we identified 107 different free energy minima. We found excellent agreement between calculated free energy minima and experimental structures of mismatches in both free DNA and DNA complexed with the MutS enzyme. The latter suggests that MutS evolved in such a way that the mismatch recognition is achieved by probing a mismatch towards the minor groove, where mismatches exhibit stable albeit energetically less favourable structures already in the free form while the canonical base pairs do not. We also found that opening of mismatch towards minor groove provides better discrimination from the canonical base pairs than previously suggested bending of DNA. This finding can be helpful in better understanding of sequence-dependent mutability or designing chemical substances targeting damaged DNA.
This research was carried out under the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustainability Programme II and the Grant Agency of the Czech Republic (GA16-11619S/2016). Computational resources were provided by the CESNET LM2015042, the CERIT Scientific Cloud LM2015085, and the IT4Innovations National Supercomputing Center LM2015070 provided under the program “Large Infrastructures for Research, Experimental Development and Innovations” by the Ministry of Education, Youth and Sports.