Abstract
Coevolving residues in a multiple sequence alignment provide evolutionary clues of biophysical interactions in 3D structure. Despite a rich literature describing amino acid coevolution within or between proteins and nucleic acid coevolution within RNA, to date there has been no direct evidence of coevolution between protein and RNA. The ribosome, a structurally conserved macromolecular machine composed of over 50 interacting protein and RNA chains, provides a natural example of RNA/protein interactions that likely coevolved. We provide the first direct evidence of RNA/protein coevolution by characterizing the mutual information in residue triplets from a multiple sequence alignment of ribosomal protein L22 and neighboring 23S RNA. We define residue triplets as three positions in the multiple sequence alignment, where one position is from the 23S RNA and two positions are from the L22 protein. We show that residue triplets with high mutual information are more likely than residue doublets to be proximal in 3D space. Some high mutual information residue triplets cluster in a connected series across the L22 protein structure, similar to patterns seen in protein coevolution. We also describe RNA nucleotides for which switching from one nucleotide to another (or between purines and pyrimidines) results in a change in amino acid distribution for proximal amino acid positions. Multiple crystal structures for evolutionarily distinct ribosome species can provide structural evidence for these differences. For one residue triplet, a pyrimidine in one species is a purine in another, and RNA/protein hydrogen bonds are present in one species but not the other. The results provide the first direct evidence of RNA/protein coevolution by using higher order mutual information, suggesting that biophysical constraints on interacting RNA and protein chains are indeed a driving force in their evolution.
Highlights
A primary cause of coevolution between residues is biophysical interactions in the corresponding folded structure
Mutual information (MI) was calculated between one nucleotide and two amino acids from bacterial multiple sequence alignments (MSAs) for the L22 protein and the large subunit RNA chain that binds to the L22 protein, the 23S
Normalizing MI has been shown to increase residue contact prediction, and an effective method to normalize MI is to report the ratio of MI to the entropy (MI/H) [20]
Summary
A primary cause of coevolution between residues is biophysical interactions in the corresponding folded structure. Coevolving positions between residues far apart in protein structure [6,7] and even in different genes [3] have been observed, hinting at the complexities of the evolutionary process. Mutual information (MI) is one of a handful of different methods used to characterize coevolution and has been successful in identifying coevolving pairs of positions in multiple sequence alignments (MSAs) [5,7,9,10]. Multiple pairs of coevolving amino acids that form a connected structure across a protein have been characterized and implicated in functional roles such as interaction surfaces [7]. Folded proteins and RNAs are dense, highly connected structures, and undoubtedly have higher-order biophysical interactions.
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