Gantchev Tsvetan G, Cecchini Sylvain, Hunting Darel J
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.
J Mol Model. 2005 Mar;11(2):141-59. doi: 10.1007/s00894-005-0238-9. Epub 2005 Feb 18.
The dynamic structure of 11-mer DNA duplexes of different sequences with or without homopyrimidine (T.T, or BrdU.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.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).d(TTG), two wobble conformations W upward arrow (alphabeta) and W downward arrow (betaalpha) are formed and exchange rapidly at 300 K. In contrast, when the central triplet is 5'd(TTT).d(ATA) (W2 duplex) wobble conformations are rarely observed at 300 K, and the T.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 (alphabeta<-->betaalpha), as is in the case when the central triplet is 5'd(TBrdUT).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).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.
通过分子动力学（MD）模拟，在200皮秒至1纳秒的时间尺度上研究了不同序列、有或无同嘧啶（T.T或BrdU.T）错配的11聚体DNA双链体的动态结构。构象分析表明，在错配双链体中，经典T.T摆动氢键配对的形成取决于相邻序列，并且在大多数情况下，存在三中心氢键和许多其他近距离跨链原子间接触。因此，在双链体W1中，其中央三联体为5'd(CTA).d(TTG)，形成了两个摆动构象W向上箭头（αβ）和W向下箭头（βα），并在300 K时快速交换。相比之下，当中央三联体为5'd(TTT).d(ATA)（W2双链体）时，在300 K时很少观察到摆动构象，并且T.T错配最常采用“扭曲”构象，带有一个基本持久的正常氢键，加上涉及一个侧翼T碱基的稳定跨链接触。然而，在高温（400 K）下，相同的W2双链体显示出两个经典摆动构象（αβ<-->βα）之间的频繁交换，就像中央三联体为5'd(TBrdUT).d(ATA)（300 K时的W3双链体）的情况一样。有人认为，在W2序列中，胸腺嘧啶甲基/π相互作用造成的限制阻止了摆动配对的形成，并且需要热活化能和/或用BrdU化学取代T，以便T(BrdU).T错配采用摆动构象并在其中交换。对W1、W2和W3双链体中特定的短寿命和/或长寿命（双/三）跨链动态相互作用进行了全面表征。这些频繁的原子相遇例证了所研究DNA分子中可能的链间电荷转移途径。
