de Ruiter Anita, Zagrovic Bojan
Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna 1030, Austria.
Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna 1030, Austria
Nucleic Acids Res. 2015 Jan;43(2):708-18. doi: 10.1093/nar/gku1344. Epub 2014 Dec 30.
Despite the great importance of nucleic acid-protein interactions in the cell, our understanding of their physico-chemical basis remains incomplete. In order to address this challenge, we have for the first time determined potentials of mean force and the associated absolute binding free energies between all standard RNA/DNA nucleobases and amino-acid sidechain analogs in high- and low-dielectric environments using molecular dynamics simulations and umbrella sampling. A comparison against a limited set of available experimental values for analogous systems attests to the quality of the computational approach and the force field used. Overall, our analysis provides a microscopic picture behind nucleobase/sidechain interaction preferences and creates a unified framework for understanding and sculpting nucleic acid-protein interactions in different contexts. Here, we use this framework to demonstrate a strong relationship between nucleobase density profiles of mRNAs and nucleobase affinity profiles of their cognate proteins and critically analyze a recent hypothesis that the two may be capable of direct, complementary interactions.
尽管核酸与蛋白质之间的相互作用在细胞中极为重要，但我们对其物理化学基础的理解仍不完整。为应对这一挑战，我们首次使用分子动力学模拟和伞形抽样，确定了在高介电和低介电环境中，所有标准RNA/DNA核碱基与氨基酸侧链类似物之间的平均力势和相关的绝对结合自由能。与一组有限的类似系统的可用实验值进行比较，证明了计算方法和所用势场的质量。总体而言，我们的分析提供了核碱基/侧链相互作用偏好背后的微观图景，并创建了一个统一的框架，用于理解和塑造不同背景下的核酸-蛋白质相互作用。在此，我们使用这个框架来证明mRNA的核碱基密度分布与其同源蛋白质的核碱基亲和力分布之间的紧密关系，并批判性地分析了最近的一个假设，即两者可能能够进行直接的互补相互作用。
