What role does molecular dynamics (MD) simulation play in understanding the bypass of 7-deazaguanine DNA-peptide lesions by human TLS polymerases?

Molecular dynamics simulations were conducted to examine how DNA-peptide lesions conjugated to the 7-deazaguanine position in DNA can be accommodated within the active site of human lesion bypass polymerase κ.

From: "Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases", JBC, Volume 291, Issue 45, November 2016, Pages 23589-23603

MD simulations reveal that the 10-mer peptide cross-link conjugated to 7-deazaguanine can be accommodated in the major groove of the DNA within the polymerase active site, allowing for high-fidelity nucleotide insertion. The simulation shows that the Watson-Crick base pairing is distorted due to the rigidity imposed by the cross-link, which likely contributes to inefficient lesion bypass and polymerase stalling. The study suggests that the size and orientation of the peptide conjugated to 7-deazaguanine are critical factors in determining the ability of TLS polymerases to bypass these lesions.