Isaacs Richard J, Spielmann H Peter
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0084, USA.
J Am Chem Soc. 2004 Jan 21;126(2):583-90. doi: 10.1021/ja037333r.
Molecular dynamics (MD) simulations were conducted for a G[bond]T mismatch-containing DNA decamer, d(CCATGCGTGG)(2), and its Watson-Crick parent sequence, d(CCACGCGTGG)(2). Dynamics in unrestrained MD trajectories were in poor agreement with prior (13)C NMR studies. However, the accuracy of the trajectories was improved by the use of time-averaged interatomic distance restraints derived from (1)H NMR. Postprocess smoothing of the trajectories further improved accuracy. Comparison of restrained and smoothed trajectories of the two DNA molecules revealed distinct differences in dynamics. The major groove width of the mismatched oligomer was more variable over the course of the simulation compared to its parent sequence. Greater variability in helical parameters stretch and opening for the mismatches indicated less kinetically stable base pairing. Interbase helical parameters rise, roll, and tilt were also more variable in certain base steps involving mismatched bases. These dynamic differences between normal and G[bond]T mismatched DNA reflect differences in local flexibility that may play a role in mismatch recognition by the MutS. A potential alternate G[bond]T mismatch binding mode for MutS is also proposed.
对含有G[键]T错配的DNA十聚体d(CCATGCGTGG)(2)及其沃森-克里克亲本序列d(CCACGCGTGG)(2)进行了分子动力学(MD)模拟。无约束MD轨迹中的动力学与先前的(13)C NMR研究结果不一致。然而，通过使用源自(1)H NMR的时间平均原子间距离约束，轨迹的准确性得到了提高。轨迹的后处理平滑进一步提高了准确性。对两个DNA分子的约束和平滑轨迹进行比较，发现动力学存在明显差异。与亲本序列相比，错配寡聚物的大沟宽度在模拟过程中变化更大。错配的螺旋参数伸展和开口的更大变异性表明碱基配对的动力学稳定性较低。在涉及错配碱基的某些碱基步中，碱基间螺旋参数上升、滚动和倾斜也更具变异性。正常DNA和G[键]T错配DNA之间的这些动态差异反映了局部灵活性的差异，这可能在MutS识别错配中起作用。还提出了MutS潜在的替代G[键]T错配结合模式。
