Book of Abstracts: Albany 2005
DNA Triplex Bending Induced by Nonisomorphic Base Triplets
Recently (1), it has been suggested by us that the base triplet non-isomorphism may be articulated in structural terms by a residual twist (Δt°), the angle formed by line joining the C1'...C1' atoms of the adjacent Hoogsteen or reverse Hoogsteen (RH) base pairs, and the difference in base triplet radius (Δr Å), and that (ii) their influence on DNA triplex is largely mechanistic, leading to the prediction of a high (t +Δt)° and low (t +Δt)° twist at alternating steps of Hoogsteen or RH duplex of a parallel or antiparallel triplex. Efficacy of this concept has been corroborated by molecular dynamics (MD) simulations of an antiparallel DNA triplex comprising alternating non-isomorphic G*GC and T*AT triplets. Conformational changes necessitated by base triplet non-isomorphism are found to induce in addition an alternating (i) high anti and anti glycosyl and (ii) BII and an unusual BIII conformation resulting in a zigzag backbone for the RH strand. Essentially similar results are also found in antiparallel DNA triplex comprising alternating non-isomorphic G*GC and A*AT triplets. Interestingly, the highest value of residual twist (Δt ∼21°) found between the nonisomorphic parallel G*GC and T*AT triplets, destabilises the canonical Hoogsteen G*GC hydrogen bond into several noncanonical forms, thus providing a possible stereochemical rationale for the experimentally observed inability to realize parallel DNA triplex with frequent interspersion of G*GC and T*AT triplets. On the other hand, nonisomorphic G*GC and T*AT base triplets are tolerated as the base triplet mismatches in homopolymeric T*AT and G*GC triplexes. Most interestingly, it is found that phasing of parallel mini G*GC and T*AT triplexes induces bending at non-isomorphic base triplet steps. The high value of residual Hoogsteen twist (Δt = ∼21°') together with the need to bridge the gap (in the Hoogsteen strand) arising out of large differences (>3A) in the groove widths of G*GC and T*AT triplexes appear to the sources for triplex bending. Seemingly then, it is possible to induce bending in a DNA duplex with untethered TFOs too, in addition to tethered TFOs (2, 3).
References and Footnotes
Institute of Bioinformatics and Applied Biotechnology