Abstract
Many critical processes in the cell involve direct binding between RNAs and proteins, making it imperative to fully understand the physicochemical principles behind such interactions at the atomistic level. Here, we use molecular dynamics simulations and 15 μs of sampling to study the behavior of amino acids and amino acid sidechain analogs in high-concentration aqueous solutions of standard RNA nucleobases. Structural and energetic analysis of simulated systems allows us to derive interaction propensity scales for different amino acid/nucleobase combinations. The derived scales closely match and greatly extend the available experimental data, providing a comprehensive foundation for studying RNA–protein interactions in different contexts. By using these scales, we demonstrate a statistically significant connection between nucleobase composition of human mRNA coding sequences and nucleobase interaction propensities of their cognate protein sequences. For example, pyrimidine density profiles of mRNAs match uracil-propensity profiles of their cognate proteins with a median Pearson correlation coefficient of R = −0.70. Our results provide support for the recently proposed hypotheses that mRNAs and their cognate proteins may be physicochemically complementary to each other and bind, especially if unstructured, with the complementarity level being negatively influenced by mRNA adenine content. Finally, we utilize the derived scales to refine the complementarity hypothesis and closely examine its physicochemical underpinnings.
Highlights
From transcriptional and translational regulation to RNA processing and decay to protein localization, many key processes in the cell depend directly on RNA–protein interactions [1,2,3,4]
In order to better understand the underlying physicochemical principles behind RNA–protein interactions and shed more light on the mRNA/protein complementarity hypothesis, here we systematically explore the behavior of individual amino acids and amino acid sidechain analogs in high-concentration aqueous solutions of different RNA nucleobases using classical molecular dynamics (MD) simulations (Figure 1A)
This suggests that our systems would over long timescales likely result in a creation of macroscopic aggregates, they are thermodynamically stable on the sizeand time scales examined here and could be used as model systems to study the behavior of amino acids and their sidechain analogs in aqueous solutions of nucleobases
Summary
From transcriptional and translational regulation to RNA processing and decay to protein localization, many key processes in the cell depend directly on RNA–protein interactions [1,2,3,4]. One may expect that integrative efforts involving biochemical, structural and computational techniques will soon catalog most if not all of biologically relevant RNA–protein interactions. Only a few experimental studies have been performed in order to directly explore interactions between individual nucleobases and amino acids in different environments [7,8,9,10]. While global and local structural contexts do play important roles in defining the properties of RNA–protein binding interfaces, it is reasonable to expect that binding specificity in general critically depends on the preferences of individual nucleobases and amino acids for each other
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