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

Abstract

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.

Figure 1

Evolution of proteins under selection for folding to maintain a function. The proteins exist in a population, the size of which determines the relative influences of drift and selection. The ancestral allele (green) is modified by mutation to deleterious (red) and nearly-neutral (blue) derived alleles, which are ultimately eliminated or fixed by selection or by drift randomly. Ancestral alleles are not always lost and derived alleles not always fixed. The process is stochastic rather than deterministic, described by the interplay of the strength of selection and population level dynamics. The figure is derived from PDB structures 1D4T (chain A), 1QG1 (chain E), and 1JD1 (chain A), which are used for illustrative purposes. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Symmetries of homomeric protein complexes. Complexes on the left hand side have cyclic symmetry (C_n), which means all subunits are related by rotation around a single n-fold rotation axis. Complexes on the right hand side have dihedral symmetry (D_n), which means they have an n-fold rotation axis that intersects a 2-fold rotation axis at right angles. Homomers have either symmetric face-to-face (e.g., a C2 homodimer, PDB: 1QZT), or asymmetric face-to-back interfaces (e.g., a C3 homotrimer, PDB: 1G2X, or a C4 homotetramer, PDB: 1PQF). Symmetric interfaces result in complexes with dihedral symmetry, while asymmetric interfaces imply homomeric complexes with cyclic symmetry. Symmetric interfaces evolve more readily than asymmetric ones and thus there are more dihedral than cyclic complexes (see text). During the course of evolution, proteins can evolve multiple interfaces and form higher oligomers, such as trimers of dimers (D3, PDB: 1NLS); or dimers of trimers (D3, PDB: 1V9L) or tetramers (D4, PDB: 1HAN). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

Hypothetical evolution of sequences and folds. On short time scales, mutations and selection due to protein fold (A) cause emergence of a closely related family of protein sequences (A1-A6). On longer time scales, sequences occasionally cross (yellow arrows) the larger free energy barriers that separate related folds (B, C) in sequence space and establish novel sequence families (B1-C6). This figure is modified from a figure published in Ref.. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 4

The largest component of the Protein Domain Universe Graph (PDUG) shows the structure of domain relationships and its interconnectedness based upon structural geometries. This figure has previously been published in and is reproduced with copyright permission from Landes Bioscience and Springer Science+Business Media.