Goh Garrett B, Knight Jennifer L, Brooks Charles L
Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, Michigan 48109, United States.
J Phys Chem Lett. 2013 Mar 7;4(5):760-766. doi: 10.1021/jz400078d. Epub 2013 Feb 12.
The role of protonated nucleotides in modulating the pH-dependent properties of nucleic acids is one of the emerging frontiers in the field of nucleic acid biology. The recent development of a constant pH molecular dynamics simulation (CPHMD) framework for simulating nucleic acids has provided a tool for realistic simulations of pH-dependent dynamics. We enhanced the CPHMD framework with pH-based replica exchange (pH-REX), which significantly improves the sampling of both titration and spatial coordinates. The results from our pK calculations for the GAAA tetraloop, which was predicted with lower accuracy previously due to sampling challenges, demonstrates that pH-REX reduces the average unsigned error (AUE) to 0.7 pK units, and the error of the most poorly predicted residue A17 was drastically reduced from 2.9 to 1.2 pK unit. Lastly, we show that pH-REX CPHMD simulations can be used to identify the dominant conformation of nucleic acid structures in alternate pH environments. This work suggests that pH-REX CPHMD simulations provide a practical tool for predicting nucleic acid protonation equilibrium from first-principles, and offering structural and mechanistic insight into the study of pH-dependent properties of nucleic acids.
质子化核苷酸在调节核酸pH依赖性特性中的作用是核酸生物学领域新兴的前沿之一。用于模拟核酸的恒定pH分子动力学模拟（CPHMD）框架的最新发展为pH依赖性动力学的逼真模拟提供了一种工具。我们用基于pH的副本交换（pH-REX）增强了CPHMD框架，这显著改善了滴定和空间坐标的采样。我们对GAAA四环进行的pK计算结果表明，由于采样挑战，该四环先前预测的准确性较低，而pH-REX将平均无符号误差（AUE）降低到0.7 pK单位，预测最差的残基A17的误差从2.9 pK单位大幅降低到1.2 pK单位。最后，我们表明pH-REX CPHMD模拟可用于识别不同pH环境中核酸结构的主要构象。这项工作表明，pH-REX CPHMD模拟为从第一性原理预测核酸质子化平衡提供了一种实用工具，并为研究核酸pH依赖性特性提供了结构和机制方面的见解。
