Molecular insight into how the position of an abasic site modifies DNA duplex stability and dynamics
Molecular insight into how the position of an abasic site modifies DNA duplex stability and dynamics
复制标题
DOI：
10.1016/j.bpj.2023.11.022
复制
发表时间：
2024-01-16
影响因子：
3.4
通讯作者：
Tokmakoff，Andrei
中科院分区：
文献类型：
--
作者：
Ashwood，Brennan;Jones，Michael S.;Tokmakoff，Andrei
损伤和化学修饰对DNA碱基配对稳定性的局部扰动可以改变整个寡核苷酸的稳定性和动力学。末端效应可能导致短双链体内的破坏位置影响双链体稳定性和结构动力学，但核酸修饰的这一方面常常被忽视。我们研究了脱碱基位点（AP位点）的位置如何影响短DNA双链体的稳定性和动力学。使用稳态和时间分辨光谱和分子动力学模拟的组合，我们解开AP位点的位置和核碱基序列，控制精力充沛和动态中断的双链体之间的相互作用。双链体被AP位点两侧碱基配对的熵屏障破坏成两段。当AP位点靠近末端时，屏障诱导短片段的磨损。向内移动AP位点促进了从短片段磨损到完全包围杂交热力学屏障的过渡，导致双链体的进一步不稳定。核碱基序列通过调节短片段的势垒高度和碱基对稳定性来确定该转变的长度尺度，并且某些序列使得配准外碱基配对能够使势垒高度最小化。
Local perturbations to DNA base-pairing stability from lesions and chemical modifications can alter the stability and dynamics of an entire oligonucleotide. End effects may cause the position of a disruption within a short duplex to influence duplex stability and structural dynamics, yet this aspect of nucleic acid modifications is often overlooked. We investigate how the position of an abasic site (AP site) impacts the stability and dynamics of short DNA duplexes. Using a combination of steady-state and time-resolved spectroscopy and molecular dynamics simulations, we unravel an interplay between AP-site position and nucleobase sequence that controls energetic and dynamic disruption to the duplex. The duplex is disrupted into two segments by an entropic barrier for base-pairing on each side of the AP site. The barrier induces fraying of the short segment when an AP site is near the termini. Shifting the AP site inward promotes a transition from short-segment fraying to fully encompassing the barrier into the thermodynamics of hybridization, leading to further destabilization of the duplex. Nucleobase sequence determines the length scale for this transition by tuning the barrier height and base-pair stability of the short segment, and certain sequences enable out-of-register base-pairing to minimize the barrier height.