Mondal Manas, Gao Yi Qin
Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, 518107 Shenzhen, China.
Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China.
J Phys Chem Lett. 2022 Jun 3:5109-5115. doi: 10.1021/acs.jpclett.2c00640.
Gene regulatory functions of noncanonical i-motif DNA are associated with dynamic i-motif formation in the cellular environment and pH variation. With atomistic simulations, we show the dramatic influence of solvent pH on the conformational dynamics of biologically relevant telomeric i-motif DNA coupled with protonation of cytosine bases in different conformations. We rationalized the pH-dependent dynamics and conformational variability of the i-motif in terms of base pairing and specific loop motions. The human telomeric i-motif is found to acquire various metastable folded conformations at pH values near the p of cytosine with the formation of a noncanonical C:C W:W trans base pair along with the hemiprotonated C:C pairs in the i-motif core. pH-dependent dynamics and the local solvent structure of i-motif DNA imply that the presence of a cosolvent or molecular crowding can promote i-motif formation by changing the conformational fluctuations and hydration state of the structure.
非经典i-基序DNA的基因调控功能与细胞环境中动态的i-基序形成及pH变化相关。通过原子模拟，我们展示了溶剂pH对具有生物学相关性的端粒i-基序DNA构象动力学的显著影响，以及不同构象中胞嘧啶碱基质子化的情况。我们根据碱基配对和特定的环运动，对i-基序的pH依赖性动力学和构象变异性进行了合理化解释。研究发现，人类端粒i-基序在接近胞嘧啶pKa值的pH下会获得各种亚稳态折叠构象，同时在i-基序核心形成非经典的C:C W:W反式碱基对以及半质子化的C:C对。i-基序DNA的pH依赖性动力学和局部溶剂结构表明，共溶剂的存在或分子拥挤可通过改变结构的构象波动和水合状态来促进i-基序的形成。
