Epistasis in protein evolution

Abstract

The structure, function, and evolution of proteins depend on physical and genetic interactions among amino acids. Recent studies have used new strategies to explore the prevalence, biochemical mechanisms, and evolutionary implications of these interactions-called epistasis-within proteins. Here we describe an emerging picture of pervasive epistasis in which the physical and biological effects of mutations change over the course of evolution in a lineage-specific fashion. Epistasis can restrict the trajectories available to an evolving protein or open new paths to sequences and functions that would otherwise have been inaccessible. We describe two broad classes of epistatic interactions, which arise from different physical mechanisms and have different effects on evolutionary processes. Specific epistasis-in which one mutation influences the phenotypic effect of few other mutations-is caused by direct and indirect physical interactions between mutations, which nonadditively change the protein's physical properties, such as conformation, stability, or affinity for ligands. In contrast, nonspecific epistasis describes mutations that modify the effect of many others; these typically behave additively with respect to the physical properties of a protein but exhibit epistasis because of a nonlinear relationship between the physical properties and their biological effects, such as function or fitness. Both types of interaction are rampant, but specific epistasis has stronger effects on the rate and outcomes of evolution, because it imposes stricter constraints and modulates evolutionary potential more dramatically; it therefore makes evolution more contingent on low-probability historical events and leaves stronger marks on the sequences, structures, and functions of protein families.

Long-Range Epistasis Mediated by Structural Change in a Model of Ligand Binding Proteins

“…Alternatively, neutral, or slightly deleterious mutations that preserve the native structure can conspire to frustrate formation of the binding site during folding. In this case, a mutation that increases the energy of the native fold relative to mis–folded states, or provides for greater conformational freedom during folding, amplifies the negative effect of a second mutation, presumably as a result of proximity to a thermodynamic phase transition [1, 2]. We find, however, that this process does not necessarily result in a complete change of phase.…”

“…Epistasis in protein biophysics refers to the non–additive effects of amino acid mutations on protein folding and function [1]. An epistatic interaction is said to occur between two mutations when their combined effect on a trait is either larger or smaller than the sum of their effects considered independently.…”

“…Conversely, mutations that have a neutral, or nearly neutral effect on function individually, may produce a damaging effect in combination—a form of negative epistasis. Recent analyses of amino acid mutations in proteins reveal that mutations at many pairs of sites are epistatic, and suggest that epistasis plays a significant role in protein evolution [1–13]. Interestingly, epistatic sites are not necessarily in contact with each other in the folded state of a protein, and may even be located on opposite sides of a molecule.…”

Evolution of protein specificity: insights from ancestral protein reconstruction

“…First, the specific biological functions of extant proteins have in some cases emerged de novo following gene duplications; although such de novo trajectories are not the most frequent kind of history observed, they can and do occur. Second, when new specific interactions with molecular partners evolved, they did so through a small number of large-effect substitutions, with other historical sequences changes exerting permissive, fine-tuning, or inconsequential effects [50–52]. Third, the mechanisms by which these large-effect substitutions conferred new functions were relatively simple, involving steric clashes and changes in polar interactions between protein and ligand.…”

A Shorter Route to Antibody Binders via Quantitative in vitro Bead-Display Screening and Consensus Analysis

“…The residue V L Y50 (numbered according to the Kabat system44) was the only position that did not have a clearly dominating mutation, and the tyrosine was mutated either to serine or histidine (covering 50% or 48% of mutations occurring in this position, respectively). This observation of two alternative residues in position V L Y50 raised the possibility of deleterious negative epistatic interactions454647 between these residues and other mutations and suggested a another possible driving force behind selection of either histidine or serine in this position. This bifurcation in the evolutionary history of the final variants48 would be indicative of a rugged fitness landscape4950.…”