Sequence dependent influence of an A…A mismatch in a DNA duplex: An insight into the recognition by hZαADAR1 protein

Abstract

Base pair mismatches can erroneously be incorporated in the DNA. An adenine pairing with another adenine is one of the eight possible mismatches. The atomistic insights about the structure and dynamics of an A…A mismatch in a DNA (unbound form) is not yet accessible to any experimental technique. Earlier molecular dynamics (MD) simulations have shown that A…A mismatch in the midst of 5′CAG/3′GAC, 5′GAC/3′CAG and 5′CAA/3′GAT (underline represents the mismatch) are highly dynamic in nature. By employing MD simulation, the influence of an A…A mismatch in the midst of 5′GAA/3′CAT, 5′GAG/3′CAC, 5′AAC/3′TAG, 5′AAG/3′TAC, 5′TAA/3′AAT, 5′TAT/3′AAA and 5′AAT/3′TAA sequences have been investigated here. The results indicate that irrespective of the flanking sequences, the mismatch samples a variety of transient conformations, including a B-Z junction. Further, circular dichroism studies have been carried out to explore the ability of these sequences to bind with hZαADAR1 which specifically recognizes B-Z junction/Z-DNA. The results indicate that hZαADAR1 could not lead to a complete B to Z transition in the above sequences. Notably, a complete transition to Z-form has been reported earlier for 5′GAC/3′CAG upon titrating with hZαADAR1. Intriguingly, 5′AAC/3′TAG, 5′AAG/3′TAC and 5′GAA/3′CAT exhibit a B-Z junction formation rather than a complete transition to Z-form, similar to the situation of 5′CAA/3′GAT. These indicate that although A…A mismatch could induce a local B-Z junction transiently, hZαADAR1 requires the presence of a G…C/C…G base pair adjacent to the A…A mismatch for the binding. Additionally, the extent of B-Z junction has enhanced upon binding with hZαADAR1 in the presence of the A…A mismatch (specifically when CG, CA, AC, GA and AG steps occur), but not in the presence of the canonical base pairs. These confirm the inclination of A…A mismatch towards the B-Z junction.