title: Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family.
abstract: Viral capsids are structurally constrained by interactions among the amino acids (AAs) of their constituent proteins. Therefore, epistasis is expected to evolve among physically interacting sites and to influence the rates of substitution. To study the evolution of epistasis, we focused on the major structural protein of the ϕX174 phage family by first reconstructing the ancestral protein sequences of 18 species using a Bayesian statistical framework. The inferred ancestral reconstruction differed at eight AAs, for a total of 256 possible ancestral haplotypes. For each ancestral haplotype and the extant species, we estimated, in silico, the distribution of free energies and epistasis of the capsid structure. We found that free energy has not significantly increased but epistasis has. We decomposed epistasis up to fifth order and found that higher-order epistasis sometimes compensates pairwise interactions making the free energy seem additive. The dN/dS ratio is low, suggesting strong purifying selection, and that structure is under stabilizing selection. We synthesized phages carrying ancestral haplotypes of the coat protein gene and measured their fitness experimentally. Our findings indicate that stabilizing mutations can have higher fitness, and that fitness optima do not necessarily coincide with energy minima.
authors.affiliation: IST Austria, Am Campus 1, 3400 Klosterneuburg, Austria.
authors.forename: Rodrigo A F
authors.identifier: 0000-0002-5837-2793
authors.initials: RA
authors.lastname: Redondo
authors.affiliation: IST Austria, Am Campus 1, 3400 Klosterneuburg, Austria harold.vladar@parmenides-foundation.org.|Center for the Conceptual Foundations of Science, Parmenides Foundation, 82049 Pullach, Germany.
authors.forename: Harold P
authors.identifier: 0000-0002-5985-7653
authors.initials: HP
authors.lastname: de Vladar
authors.affiliation: Department of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Tomasz
authors.identifier: 0000-0001-6498-334X
authors.initials: T
authors.lastname: Włodarski
authors.affiliation: IST Austria, Am Campus 1, 3400 Klosterneuburg, Austria.
authors.forename: Jonathan P
authors.identifier: 0000-0002-4624-4612
authors.initials: JP
authors.lastname: Bollback
mesh_terms: D010584:Bacteriophage phi X 174 / Q000145:classification / Q000235:genetics; D036022:Capsid Proteins / Q000235:genetics*; D019143:Evolution, Molecular; D012641:Selection, Genetic
chemical_list: D036022:Capsid Proteins
keywords: ancestral reconstruction; experimental evolution; high-order epistasis; phylogenetics; stabilizing selection; structure prediction