Abstract
Experimental studies have shown that some proteins exist in two alternative native-state conformations. It has been proposed that such bi-stable proteins can potentially function as evolutionary bridges at the interface between two neutral networks of protein sequences that fold uniquely into the two different native conformations. Under adaptive conflict scenarios, bi-stable proteins may be of particular advantage if they simultaneously provide two beneficial biological functions. However, computational models that simulate protein structure evolution do not yet recognize the importance of bi-stability. Here we use a biophysical model to analyze sequence space to identify bi-stable or multi-stable proteins with two or more equally stable native-state structures. The inclusion of such proteins enhances phenotype connectivity between neutral networks in sequence space. Consideration of the sequence space neighborhood of bridge proteins revealed that bi-stability decreases gradually with each mutation that takes the sequence further away from an exactly bi-stable protein. With relaxed selection pressures, we found that bi-stable proteins in our model are highly successful under simulated adaptive conflict. Inspired by these model predictions, we developed a method to identify real proteins in the PDB with bridge-like properties, and have verified a clear bi-stability gradient for a series of mutants studied by Alexander et al. (Proc Nat Acad Sci USA 2009, 106:21149–21154) that connect two sequences that fold uniquely into two different native structures via a bridge-like intermediate mutant sequence. Based on these findings, new testable predictions for future studies on protein bi-stability and evolution are discussed.
Highlights
New functional proteins are likely to evolve from existing proteins
A gene duplication of a multifunctional protein is more likely to be successful than duplicating a protein with only a single function: first, because a new function is already present – it does not have to first evolve the new function in a rare mutant carrying a gene duplication; second, functional divergence can be faster because the multiple functions have already been responding to conflicting selection pressures; and, retention and fixation of the duplication is more likely because the second copy can immediately provide higher activity levels through higher protein concentrations for the multiple protein functions, none of which would likely have been fully optimized in a single-gene, multi-functional protein
We investigate a fundamental question in molecular evolution: how can proteins acquire new advantageous structures via mutations while not sacrificing their existing structures that are still needed? Some authors have suggested that the same protein may adopt two or more alternative structures, switch between them and perform different functions with each of the alternative structures
Summary
New functional proteins are likely to evolve from existing proteins. Most existing proteins, are under selection to conserve their existing native structure in order to maintain functionality (and to avoid aggregation and proteolysis). When the same gene (protein) is under two selection pressures, i.e. to evolve a new functional structure while conserving its existing structure, an adaptive conflict arises. This adaptive conflict scenario is at the heart of most contemporary theories of molecular evolution, such as the popular Neofunctionalization and Subfunctionalization models (as reviewed in [1,2]). These models generally require gene duplications to take place before adaptive conflicts can be resolved. A gene duplication of a multifunctional protein is more likely to be successful than duplicating a protein with only a single function: first, because a new function is already present – it does not have to first evolve the new function in a rare mutant carrying a gene duplication; second, functional divergence can be faster because the multiple functions have already been responding to conflicting selection pressures; and, retention and fixation of the duplication is more likely because the second copy can immediately provide higher activity levels through higher protein concentrations for the multiple protein functions, none of which would likely have been fully optimized in a single-gene, multi-functional protein
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