Sund Johan, Lind Christoffer, Åqvist Johan
Department of Cell and Molecular Biology, Uppsala University , Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
J Phys Chem B. 2015 Jan 22;119(3):773-82. doi: 10.1021/jp5052358. Epub 2014 Jul 18.
The progress of RNA research has suggested a wide variety of RNA molecules as possible targets for pharmaceutical drug molecules. Structure-based computational methods for predicting binding modes and affinities are now important tools in drug discovery, but these methods have mainly been focused on protein targets. Here we employ molecular dynamics free-energy perturbation calculations and the linear interaction energy method to analyze the energetics of ligand binding to purine riboswitches. Calculations are carried out for 14 different purine complexes with the guanine and adenine riboswitches in order to examine their ligand recognition principles. The simulations yield binding affinities in good agreement with experimental data and rationalize the selectivity of the riboswitches for different ligands. In particular, it is found that these receptors have an unusually high degree of electrostatic preorganization for their cognate ligands, and this effect is further quantified by explicit free-energy calculations, which show that the standard electrostatic linear interaction energy parametrization is suboptimal in this case. The adenine riboswitch specifically uses the electrostatic preorganization to discriminate against guanine by preventing the formation of a G-U wobble base pair.
RNA研究的进展表明，多种RNA分子可能成为药物分子的作用靶点。基于结构的计算方法用于预测结合模式和亲和力，现已成为药物发现中的重要工具，但这些方法主要集中于蛋白质靶点。在此，我们采用分子动力学自由能微扰计算和线性相互作用能方法，分析配体与嘌呤核糖开关结合的能量学。针对14种不同的嘌呤复合物，分别与鸟嘌呤和腺嘌呤核糖开关进行计算，以研究它们的配体识别原理。模拟得到的结合亲和力与实验数据高度吻合，并解释了核糖开关对不同配体的选择性。特别地，发现这些受体对其同源配体具有异常高程度的静电预组织，通过显式自由能计算进一步量化了这种效应，结果表明在这种情况下标准静电线性相互作用能参数化并不理想。腺嘌呤核糖开关通过阻止G-U摆动碱基对的形成，特异性地利用静电预组织来区分鸟嘌呤。
