The Role of Evolutionary Selection in the Dynamics of Protein Structure Evolution

Abstract

Homology modeling is a powerful tool for predicting a protein's structure. This approach is successful because proteins whose sequences are only 30% identical still adopt the same structure, while structure similarity rapidly deteriorates beyond the 30% threshold. By studying the divergence of protein structure as sequence evolves in real proteins and in evolutionary simulations, we show that this nonlinear sequence-structure relationship emerges as a result of selection for protein folding stability in divergent evolution. Fitness constraints prevent the emergence of unstable protein evolutionary intermediates, thereby enforcing evolutionary paths that preserve protein structure despite broad sequence divergence. However, on longer timescales, evolution is punctuated by rare events where the fitness barriers obstructing structure evolution are overcome and discovery of new structures occurs. We outline biophysical and evolutionary rationale for broad variation in protein family sizes, prevalence of compact structures among ancient proteins, and more rapid structure evolution of proteins with lower packing density.

Molecular function limits divergent protein evolution on planetary timescales

“…Our results are consistent with this model, demonstrating that conservation of functional specificity imposes substantially more stringent long-term sequence constraints than conservation of protein folds, and thus protein stability. The preservation of structural optimality (<3Å C-alpha RMSD) required for a given molecular function leads, in agreement with the results by Chothia and Lesk [1] and others [21], to substantial levels of sequence conservation and the observed divergence limit.…”

“…The distribution of the fitted parameter Y0 suggests a long-term sequence identity >25% (with average ~40%) between considered orthologs (Figure 2a); this demonstrates that conservation of a specific enzymatic function significantly limits long-term protein sequence divergence. Notably, model 2 is mathematically equivalent (see Methods) to a divergence model with equal substitution rates across sites, a limited number of amino acid types accepted per site, and allowed back substitutions [20][21][22]. In this model, parameter Y0 represents the inverse of the effective number of acceptable amino acid types per site during protein evolution.…”

Characterization of the GPR1/FUN34/YaaH protein family in the green microalga Chlamydomonas suggests their role as intracellular membrane acetate channels

“…As acetate metabolism is a key carbon source for green algae such as C. reinhardtii , it is likely that a strong evolutionary pressure exists to maintain structural conformations which enable transport of this molecule across membranes. The structural conservation of Cr GFY proteins with SatP_Ck and SatP_Ec is within the threshold of similarity previously reported for conservation of function (Gilson, Marshall‐Christensen, Choi, & Shakhnovich, ). Indeed, key residues specifically involved in acetate interactions are conserved between the algal and bacterial channel proteins, suggesting functional similarity (Figure a,d).…”

Effect of protein structure on evolution of cotranslational folding

“…Nine lattice protein native structures were selected from the representative 10,000 structure subset of 27-mers used in previous works (40,41). Each native structure arranges the chain in a 3x3x3 cubic native fold.…”