Department of Medicinal Chemistry, College of Pharmacy, Skaggs Hall 201, University of Utah, Salt Lake City, Utah 84112, USA.
J Am Chem Soc. 2011 Sep 14;133(36):14270-9. doi: 10.1021/ja107805r. Epub 2011 Aug 19.
The lengths of G-tracts and their connecting loop sequences determine G-quadruplex folding and stability. Complete understanding of the sequence-structure relationships remains elusive. Here, single-loop G-quadruplexes were investigated using explicit solvent molecular dynamics (MD) simulations to characterize the effect of loop length, loop sequence, and G-tract length on the folding topologies and stability of G-quadruplexes. Eight loop types, including different variants of lateral, diagonal, and propeller loops, and six different loop sequences [d0 (i.e., no intervening residues in the loop), dT, dT(2), dT(3), dTTA, and dT(4)] were considered through MD simulation and free energy analysis. In most cases the free energetic estimates agree well with the experimental observations. The work also provides new insight into G-quadruplex folding and stability. This includes reporting the observed instability of the left propeller loop, which extends the rules for G-quadruplex folding. We also suggest a plausible explanation why human telomere sequences predominantly form hybrid-I and hybrid-II type structures in K(+) solution. Overall, our calculation results indicate that short loops generally are less stable than longer loops, and we hypothesize that the extreme stability of sequences with very short loops could possibly derive from the formation of parallel multimers. The results suggest that free energy differences, estimated from MD and free energy analysis with current force fields and simulation protocols, are able to complement experiment and to help dissect and explain loop sequence, loop length, and G-tract length and orientation influences on G-quadruplex structure.
G- 串及其连接环序列的长度决定了 G- 四链体的折叠和稳定性。对序列结构关系的完整理解仍然难以捉摸。在这里，使用显式溶剂分子动力学 (MD) 模拟研究了单环 G- 四链体，以表征环长度、环序列和 G- 串长度对 G- 四链体折叠拓扑和稳定性的影响。通过 MD 模拟和自由能分析考虑了八种环类型，包括横向、对角和推进器环的不同变体，以及六个不同的环序列 [d0（即在环中没有插入残基）、dT、dT(2)、dT(3)、dTTA 和 dT(4)]。在大多数情况下，自由能估计与实验观察结果吻合良好。这项工作还为 G- 四链体折叠和稳定性提供了新的见解。这包括报告观察到的左推进器环的不稳定性，这扩展了 G- 四链体折叠的规则。我们还提出了一个合理的解释，为什么人类端粒序列在 K(+)溶液中主要形成杂交-I 和杂交-II 型结构。总体而言，我们的计算结果表明，短环通常不如长环稳定，我们假设非常短环序列的极端稳定性可能源自平行多聚体的形成。结果表明，从 MD 估计的自由能差异和使用当前力场和模拟方案的自由能分析，能够补充实验，并帮助剖析和解释环序列、环长度和 G- 串长度和方向对 G- 四链体结构的影响。
