The interface of protein structure, protein biophysics, and molecular evolution

Abstract

The interface of protein structural biology, protein biophysics, molecular evolution, and molecular population genetics forms the foundations for a mechanistic understanding of many aspects of protein biochemistry. Current efforts in interdisciplinary protein modeling are in their infancy and the state-of-the art of such models is described. Beyond the relationship between amino acid substitution and static protein structure, protein function, and corresponding organismal fitness, other considerations are also discussed. More complex mutational processes such as insertion and deletion and domain rearrangements and even circular permutations should be evaluated. The role of intrinsically disordered proteins is still controversial, but may be increasingly important to consider. Protein geometry and protein dynamics as a deviation from static considerations of protein structure are also important. Protein expression level is known to be a major determinant of evolutionary rate and several considerations including selection at the mRNA level and the role of interaction specificity are discussed. Lastly, the relationship between modeling and needed high-throughput experimental data as well as experimental examination of protein evolution using ancestral sequence resurrection and in vitro biochemistry are presented, towards an aim of ultimately generating better models for biological inference and prediction.

Temperature dependence of amino acid hydrophobicities

“…Its apparent helpfulness in contributing to prediction of the locations of the common amino acids in folded proteins agrees with the well-established closepacking of amino acid side-chains in proteins, in which large and small amino acids differ in their structural requirements (35). The finding that the core/surface distributions of the 20 amino acids can be better approximated using two complementary types of solvent transfer free energies seems likely to be useful in protein design and phylogenetics (36), by identifying suitable amino acid substitutions.…”

Capturing the mutational landscape of the beta-lactamase TEM-1

“…Particularly in the case of TEM-1, the stabilizing mutation M182T has been shown to be beneficial in the hydrolysis spectrum extension of the enzyme, only when some destabilizing mutations in the active site were present (25,26). However, the in vitro stability of these enzymes with modified active site is lower than -4 kcal/mol, suggesting that the effect of M182T should be marginal, and "challenging the notion that evolution is a balance between structure and function" (36). Our estimation of a much lower in vitro stability appears to be more compatible with the apparent selective pressures for stabilizing mutations, and may therefore suggest some limitations of the in vitro estimation of stability, at least in the case of TEM-1.…”

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

“…Therefore, in recent years, there has been a drive to integrate the fields of protein biophysics and molecular evolution in order to better understand protein evolution (Harms and Thornton 2013;Liberles et al 2012;Serohijos and Shakhnovich 2014;Soskine and Tawfik 2010). One technique that has proved particularly useful in this pursuit is ancestral sequence reconstruction (ASR).…”