Absolute binding-free energies between standard RNA/DNA nucleobases and amino-acid sidechain analogs in different environments
Absolute binding-free energies between standard RNA/DNA nucleobases and amino-acid sidechain analogs in different environments
复制标题
DOI：
10.1093/nar/gku1344
复制
发表时间：
2015-01-30
影响因子：
14.9
通讯作者：
Zagrovic, Bojan
中科院分区：
文献类型：
--
作者：
de Ruiter, Anita;Zagrovic, Bojan
尽管核酸-蛋白质相互作用在细胞中非常重要，但我们对其物理化学基础的了解仍然不完整。为了应对这一挑战，我们首次利用分子动力学模拟和伞状采样确定了高介电性和低介电性环境中所有标准RNA/DNA碱基和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。与有限的一组相似系统的可用实验值的比较证明了计算方法和使用的力场的质量。总体而言，我们的分析提供了碱基/侧链相互作用偏好背后的微观图景，并为理解和塑造不同背景下的核酸-蛋白质相互作用创建了一个统一的框架。在这里，我们使用这个框架来证明mRNAs的碱基密度分布与其同源蛋白的核碱基亲和力分布之间的强烈关系，并批判性地分析了最近的一个假设，即两者可能能够直接、互补地相互作用。
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.