Abstract
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.
Highlights
Transport and translation of mRNA to transcription and modification of DNA, many different processes in the cell critically depend on direct, specific interactions between proteins and nucleic acids [1]
At each restraining distance used in umbrella sampling (US) simulations, nucleobases and sidechain analogs explore different configurations, with shorter distances expectedly resulting in more restricted configurational diversity
Despite the fundamental importance of protein-nucleic acid interactions in all known biological systems, this is to the best of our knowledge the first time that the absolute binding free energies for all combinations of standard nucleobases and amino-acid sidechain analogs have been evaluated within a single self-consistent framework
Summary
Transport and translation of mRNA to transcription and modification of DNA, many different processes in the cell critically depend on direct, specific interactions between proteins and nucleic acids [1]. Despite the clear biological importance of such interactions, our understanding of the basic physico-chemical principles that define them at the atomistic level remains incomplete. This in particular concerns the very foundation of nucleic acid–protein interactions, that is, the intrinsic binding preferences of nucleobases and amino acids for each other in different environments. When it comes to experimental work, for example, only limited progress has been made in this context. Woese et al have used chromatographic methods to systematically study interaction propensities of all 20 common amino acids and different pyridine derivatives in water [4,5,6]
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