Dynamic conformational states of DNA containing T center dot T or BrdU center dot T mispaired bases: wobble H-bond pairing versus cross-strand inter-atomic contacts
The dynamic structure of 11-mer DNA duplexes of different sequences with or without homopyrimidine (T center dot T, or BrdU center dot T) mismatches was studied by molecular dynamics ( MD) simulations on a time scale from 200 ps to 1 ns. The conformational analysis suggests that in mismatched duplexes the formation of classical T center dot T wobble H-bonding pairing is nearest-neighbor sequence-dependent and, in most cases, three-centered H-bonds and numerous alternative close cross-strand interatomic contacts exist. Thus, in duplex W1, where the central triplet is 5'd(CTA) center dot d(TTG), two wobble conformations W up arrow (alpha beta) and W down arrow (beta alpha) are formed and exchange rapidly at 300 K. In contrast, when the central triplet is 5' d( TTT) center dot d( ATA) (W2 duplex) wobble conformations are rarely observed at 300 K, and the T center dot T mispair most often adopts a "twisted'' conformation with one largely persistent normal H-bond, plus a stable cross-strand contact involving a T flanking base. However, at elevated temperature ( 400 K) the same W2 duplex shows frequent exchange between the two classical wobble conformations (alpha beta  beta alpha), as is in the case when the central triplet is 5' d(TBrdUT) center dot d(ATA) (W3 duplex at 300 K). It is suggested that in the W2 sequence, restrictions due to thymine-methyl/pi interactions prevent the formation of wobble pairing and thermal activation energy, and/or the chemical replacement of T by BrdU are required in order for the T( BrdU) center dot T mismatch to adopt and exchange between wobble conformations. The specific short and/or long-lived (double/triple) cross-strand dynamic interactions in W1, W2 and W3 duplexes are throughout characterized. These frequent atomic encounters exemplify possible inter-strand charge transfer pathways in the studied DNA molecules.
h-bond molecular dynamics dna conformation cross-strand interactions