Date Published: January 6, 2010
Publisher: Public Library of Science
Author(s): Saikat Chakrabarti, Anna R. Panchenko, Narcis Fernandez-Fuentes. http://doi.org/10.1371/journal.pone.0008591
Abstract: Understanding the residue covariations between multiple positions in protein families is very crucial and can be helpful for designing protein engineering experiments. These simultaneous changes or residue coevolution allow protein to maintain its overall structural-functional integrity while enabling it to acquire specific functional modifications. Despite the significant efforts in the field there is still controversy in terms of the preferable locations of coevolved residues on different regions of protein molecules, the strength of coevolutionary signal and role of coevolution in functional diversification.
Partial Text: According to the neutral theory of evolution, the functionality of protein with disadvantageous amino acid substitution can be restored by another amino acid substitution which compensates the first one to sustain the fitness . Such compensatory substitutions together with other factors arising due to common functional, structural and folding constraints lead to covariation between different positions in a protein family . Other positions might not coevolve because they are neutral or under positive selection. Compensatory amino acid substitutions have been described in previous works in terms of their locations in structure, physico-chemical properties – and relation to the diseases , . It has been found that interacting residues have tendency to coevolve , , – and charge compensatory substitutions might make substantial contribution to the residue coevolution –, , . Although the coevolution is difficult to detect and is rather weak in many cases, the correlated mutations have had comparative success in predicting protein secondary and tertiary structures and in some cases protein interaction partners –.
The new mass of evidence points to the importance of coevolution in shaping the protein function. Protein function is determined by interactions with other cell components and by residue-residue interactions. Residue interactions important for the protein functional integrity are conserved in evolution. At the same time proteins change their function in evolution and therefore some functional sites are under positive selection to change in order to accommodate new functional specificities. Certain variability coupled together with the strong functional constraints and the involvement in the network of interactions makes functional sites an ideal target for coevolutionary processes. Indeed, it has been shown previously that many coevolved positions are located at or near functionally important sites ,  and pathogenic missense mutations can be compensated by another mutation to restore the fitness , . Moreover, recently we showed that coevolutionary processes are directly related to functional diversification within protein families and the sites determining functional specificity often coevolve .