Bending of Canonical and G/T Mismatched DNAs

Abstract

Mismatched base pairs alter the flexibility and intrinsic curvature of DNA. The role of such DNA features is not fully understood in the mismatch repair pathway. MutS/DNA complexes exhibit DNA bending, PHE intercalation, and changes of base-pair parameters near the mismatch. Recently, we have shown that base-pair opening in the absence of MutS can discriminate mismatches from canonical base pairs better than DNA bending. However, DNA bending in the absence of MutS was found to be rather challenging to describe correctly. Here, we present a computational study on the DNA bending of canonical and G/T mismatched DNAs. Five types of geometric parameters covering template-based bending toward the experimental DNA structure, global, and local geometry parameters were employed in biased molecular dynamics in the absence of MutS. None of these parameters showed higher discrimination than the base-pair opening. Only roll could induce a sharply localized bending of DNA as observed in the experimental MutS/DNA structure. Further, we demonstrated that the intercalation of benzene mimicking PHE decreases the energetic cost of DNA bending without any effect on mismatch discrimination.

The Importance of Charge Transfer and Solvent Screening in the Interactions of Backbones and Functional Groups in Amino Acid Residues and Nucleotides

“…MutS detects errors induced in the DNA replication by DNA polymerases. The complex of a part of this enzyme with a DNA helix was studied by Bouchal et al [ 50 ] using MD simulations, and this trajectory was used in this work to extract relevant snapshots for conducting QM calculations.…”

“…From the 50 ns MD trajectory [ 50 ], one snapshot per 10 ps was extracted (5000 snapshots in total). This set of snapshots was used to analyze structural changes in the trajectory.…”

“…In this work, the ff14SB [ 63 ] and Parmbsc1 [ 64 ] parameters were used for the protein and DNA, respectively, the same parameters as in the MD trajectory [ 50 ].…”

“… a Atoms A ∈ first base and B ∈ second base are the atom names used in the PDB file. b Base pairs are embedded in the solvated protein–DNA complex, from the MD trajectory [ 50 ] processed in this work. c RI-MP2/TRVPP geometries optimized in a vacuum [ 35 ].…”

Computational Modeling of DNA 3D Structures: From Dynamics and Mechanics to Folding

“…In addition, MD simulations can be used to reproduce the effect of base modifications or base-pair mutations on DNA flexibility [ 75 , 76 ]. For example, Aksimentiev et al combined MD simulations (using the NAMD program with a CHARMM36 force field) with a single-molecule cyclization assay to study how different cytosine modifications influence the physical properties of dsDNA (70 bp).…”