Melanism in plumage color is often associated to the single nucleotide polymorphism of the melanocortin-1-receptor (MC1R). Despite the striking association between the substitution of a Glutamic-acid by for a Lysine at position 92 on the MC1R protein and a completely black plumage, an in-depth understanding of the effect of missense mutations on the conformational change and behavior of the MC1R in the lipid bilayer caused by the absence of a crystal structure is lacking. We examine the structural basis for receptor activation using DNA sequences from the GenBank to perform in silicoprotein homology-based modeling. Our tridimensional model shows that the Alanine for a 179-Threoninesubstitution is a structural complement of the charge-reversing effect associated to the substitution of a Glutamic-acid by for a Lysine at position 92 on the MC1R. We proposed the possibility of gradual evolution in stability and electrostatic properties of the MC1R by the sequential accumulation of these two rare substitutions. These two rare substitutions further perturb physical-chemical properties that may be necessary folding requirements of the constitutively active MC1R forms without altering of ligand binding affinity. The computational coarse-grained molecular dynamics of the MC1R binding affinities to the melanocyte-stimulating hormone predicted the disparity in ligand binding amongalleles. We speculate that the disparity in structural constraints and ligand binding among the alleles within heterozygous individuals may contribute as a mechanism to the plumage color variation in the Coereba flaveola.
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