An Evolutionary Based Strategy for Predicting Rational Mutations in G Protein-Coupled Receptors

Capturing conserved patterns in genes and proteins is important for inferring phenotype prediction and evolutionary analysis. The study is focused on the conserved patterns of the G protein-coupled receptors, an important superfamily of receptors. Olfactory receptors represent more than 2% of our genome and constitute the largest family of G protein-coupled receptors, a key class of drug targets. As no crystallographic structures are available, mechanistic studies rely on the use of molecular dynamic modelling combined with site-directed mutagenesis data. In this paper, we hypothesized that human-mouse orthologs coding for G protein-coupled receptors maintain, at speciation events, shared compositional structures independent, to some extent, of their percent identity as reveals a method based in the categorization of nucleotide triplets by their gross composition. The data support the consistency of the hypothesis, showing in ortholog G protein-coupled receptors the presence of emergent shared compositional structures preserved at speciation events. An extreme bias in synonymous codon usage is observed in both the conserved and non-conserved regions of many of these receptors that could be potentially relevant in codon optimization studies. The analysis of their compositional structures would help to design new evolutionary based strategies for rational mutations that would aid to understand the characteristics of individual G protein-coupled receptors, their subfamilies and the role in many physiological and pathological processes, supplying new possible drug targets.