Abstract
A key challenge in evolutionary biology is the accurate quantification of selective pressure on proteins and other biological macromolecules at single-site resolution. The evolutionary importance of a protein site under purifying selection is typically measured by the degree of conservation of the protein site itself. A possible alternative measure is the strength of the site-induced conservation gradient in the rest of the protein structure. However, the quantitative relationship between these two measures remains unknown. Here, we show that despite major differences, there is a strong linear relationship between the two measures such that more conserved protein sites also induce stronger conservation gradient in the rest of the protein. This linear relationship is universal as it holds for different types of proteins and functional sites in proteins. Our results show that the strong selective pressure acting on the functional site in general percolates through the rest of the protein via residue-residue contacts. Surprisingly however, catalytic sites in enzymes are the principal exception to this rule. Catalytic sites induce significantly stronger conservation gradients in the rest of the protein than expected from the degree of conservation of the site alone. The unique requirement for the active site to selectively stabilize the transition state of the catalyzed chemical reaction imposes additional selective constraints on the rest of the enzyme.
Highlights
The evolutionary importance of protein sites under purifying selection can be quantified in two very different ways
Catalytic sites were shown to induce a strong gradient of conservation such that the closer a residue is to the catalytic site, the more conserved it is
We show that there is a universal linear relationship between the degree of evolutionary conservation of a protein site and the conservation gradient it induces in the protein tertiary structure, applicable to all types of sites
Summary
The evolutionary importance of protein sites under purifying selection can be quantified in two very different ways. Protein residues experience different degrees of selective pressure as a result of the different roles they play in protein stability and function[1,2]. Residues in a protein core are generally under stronger selective pressure than surface residues due to their importance in stabilizing the protein. Structural determinants such as solvent exposure[3,4,5,6,7] and degree of packing [8,9,10] were shown to explain a large portion of the variability in the observed site-specific evolutionary rates. Residues in functional sites such as catalytic sites[11] and ligand-binding sites are under stronger selective pressure than non-functional residues
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