Abstract
An understanding of the forces shaping protein conservation is key, both for the fundamental knowledge it represents and to allow for optimal use of evolutionary information in practical applications. Sequence conservation is typically examined at one of two levels. The first is a residue-level, where intra-protein differences are analyzed and the second is a protein-level, where inter-protein differences are studied. At a residue level, we know that solvent-accessibility is a prime determinant of conservation. By inverting this logic, we inferred that disordered regions are slightly more solvent-accessible on average than the most exposed surface residues in domains. By integrating abundance information with evolutionary data within and across proteins, we confirmed a previously reported strong surface-core association in the evolution of structured regions, but we found a comparatively weak association between disordered and structured regions. The facts that disordered and structured regions experience different structural constraints and evolve independently provide a unique setup to examine an outstanding question: why is a protein’s abundance the main determinant of its sequence conservation? Indeed, any structural or biophysical property linked to the abundance-conservation relationship should increase the relative conservation of regions concerned with that property (e.g., disordered residues with mis-interactions, domain residues with misfolding). Surprisingly, however, we found the conservation of disordered and structured regions to increase in equal proportion with abundance. This observation implies that either abundance-related constraints are structure-independent, or multiple constraints apply to different regions and perfectly balance each other.
Highlights
During the course of evolution, mutations arise throughout genomes and can impact every protein at every site
Confirming the “hydrophobic bonding” intuition of Kauzmann (Kauzmann, 1959) and relying on calculations of molecular surfaces based on the algorithm of Lee and Richards (1971), Chothia estimated that each square Ångstrom of accessible surface removed from contact with water provides a free energy gain of 25 cal
He provided universal relationships governing protein folding, e.g., on the proportion of the total accessible surface of a polypeptide chain that becomes buried upon folding (Chothia, 1975). This simple relationship has a profound meaning with respect to surface-to-volume ratios in folded proteins, notably that longer proteins should fold following a beads-on-a-string model rather than by forming larger beads (Wetlaufer, 1973) – it was soon realized that beads are fundamental units of protein evolution (Chothia, 1992; Murzin et al, 1995; Bateman et al, 2002; Gough and Chothia, 2002)
Summary
During the course of evolution, mutations arise throughout genomes and can impact every protein at every site. Amino-acid residues within proteins are subject to functional, biophysical, and structural constraints that are interconnected These constraints result in different degrees of purifying selection along the sequence (i.e., purging of deleterious mutations by natural selection), which yields different levels of positional conservation. He provided universal relationships governing protein folding, e.g., on the proportion of the total accessible surface of a polypeptide chain that becomes buried upon folding (Chothia, 1975) This simple relationship has a profound meaning with respect to surface-to-volume ratios in folded proteins, notably that longer proteins should fold following a beads-on-a-string model rather than by forming larger beads (Wetlaufer, 1973) – it was soon realized that beads (domains) are fundamental units of protein evolution (Chothia, 1992; Murzin et al, 1995; Bateman et al, 2002; Gough and Chothia, 2002). Considering that structures are globally maintained during the course of evolution, it is intuitive that buried residues, which contribute to folding and stability more than surface residues (Creighton and Chothia, 1989; Lim and Sauer, 1989; Tokuriki et al, 2007), are more conserved (Koshi and Goldstein, 1995; Goldman et al, 1998; Guo et al, 2004; Bloom et al, 2006; Sasidharan and Chothia, 2007; Goldstein, 2008; Conant and Stadler, 2009; Franzosa and Xia, 2009; Liberles et al, 2012; Yeh et al, 2014; Echave et al, 2015; Shahmoradi and Wilke, 2016; Spielman and Wilke, 2016; Echave and Wilke, 2017; Liu et al, 2017)
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