Department of Chemistry and Chemical Biology , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States.
Laboratory for Biomolecular Simulation Research , Rutgers, The State University of New Jersey , New Brunswick , New Jersey 08901 , United States.
J Am Chem Soc. 2019 Feb 13;141(6):2435-2445. doi: 10.1021/jacs.8b11474. Epub 2019 Jan 29.
Site binding of ions and water shapes nucleic acids folding, dynamics, and biological function, complementing the more diffuse, nonspecific "territorial" ion binding. Unlike territorial binding, prediction of site-specific binding to nucleic acids remains an unsolved challenge in computational biophysics. This work presents a new toolset based on the 3D-RISM molecular solvation theory and topological analysis that predicts cation and water site binding to nucleic acids. 3D-RISM is shown to accurately capture alkali cations and water binding to the central channel, transversal loops, and grooves of the Oxytricha nova's telomeres' G-quadruplex ( Oxy-GQ), in agreement with high-resolution crystallographic data. To improve the computed cation occupancy along the Oxy-GQ central channel, it was necessary to refine and validate new cation-oxygen parameters using structural and thermodynamic data available for crown ethers and ion channels. This single set of parameters that describes both localized and delocalized binding to various biological systems is used to gain insight into cation occupancy along the Oxy-GQ channel under various salt conditions. The paper concludes with prospects for extending the method to predict divalent cation binding to nucleic acids. This work advances the forefront of theoretical methods able to provide predictive insight into ion atmosphere effects on nucleic acids function.
离子和水在核酸折叠、动力学和生物学功能上的结合方式形成了特定的结合区域，补充了更为弥散、非特异性的“区域”离子结合。与区域结合不同，对核酸的特定结合位点的预测仍然是计算生物物理学中的一个未解决的挑战。本工作提出了一个新的工具集，基于 3D-RISM 分子溶剂化理论和拓扑分析，用于预测阳离子和水与核酸的结合位点。结果表明，3D-RISM 能够准确地捕捉到碱金属阳离子和水与栉毛虫 novae 端粒 G-四链体（Oxy-GQ）中心通道、横向环和沟槽的结合，与高分辨率晶体学数据一致。为了提高在 Oxy-GQ 中心通道中计算出的阳离子占有率，需要使用冠醚和离子通道中可用的结构和热力学数据来改进和验证新的阳离子-氧参数。这组单一的参数可以描述局部和非局部结合到各种生物系统，用于深入了解各种盐条件下 Oxy-GQ 通道中阳离子的占有率。本文最后展望了将该方法扩展到预测二价阳离子与核酸结合的前景。这项工作推进了理论方法的前沿，能够为离子气氛对核酸功能的影响提供预测性的见解。
