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

Abstract

Recent analyses of amino acid mutations in proteins reveal that mutations at many pairs of sites are epistatic—i.e., their effects on fitness are non—additive—the combined effect of two mutations being significantly larger or smaller than the sum of their effects considered independently. Interestingly, epistatic sites are not necessarily near each other in the folded structure of a protein, and may even be located on opposite sides of a molecule. However, the mechanistic reasons for long–range epistasis remain obscure. Here, we study long–range epistasis in proteins using a previously developed model in which off–lattice polymers are evolved under ligand binding constraints. Epistatic effects in the model are qualitatively similar to those recently reported for small proteins, and many are long–range. We find that a major reason for long–range epistasis is conformational change—a recurrent theme in both positive and negative epistasis being the transfer, or exchange of material between the ordered nucleus, which supports the binding site, and the liquid–like surface of a folded molecule. These local transitions in phase and folded structure are largely responsible for long–range epistasis in our model.

Beyond stability constraints: a biophysical model of enzyme evolution with selection for stability and activity

“…The very few studies that consider selection on activity focus on ligand binding [13]. Ligand-binding constraints may lead to longrange epistasis [45], which is consistent with the rate-d active dependence found for enzymes. However, rather than ligand binding, the key to enzymatic activity is lowering the activation energy barrier of the catalyzed reaction.…”

Inference of epistatic effects in a key mitochondrial protein

“…Epistasis in protein biophysics refers to the nonadditive effects of amino acid mutations on a fitness trait [1], such as folding to a functional native state supporting a specific active site structure [2,3]. For example, a deleterious mutation that disrupts folding may alter the statistical balance among conformation states available to a protein in such a way that a second, formerly deleterious mutation becomes beneficial in the new background [3], and the combined effect of the two mutations is nearly neutral -a form of positive, or compensatory epistasis [4]. Alternatively, mutations that are neutral, or nearly neutral individually may disrupt folding in combination -a form of negative epistasis.…”

How often do Protein Genes Navigate Valleys of Low Fitness?

“…Epistatic effects play an essential part in protein evolution [19–24], and because these effects depend on the relative probabilities of conformations in protein ensembles [25–27], it is important to select a model in which the salient properties of protein ensembles are retained as much as possible. Ultimately, we found that we could obtain sufficient data for valley crossing statistics in a reasonable period of time using small lattice proteins.…”