Abstract
What is the architectural “basis set” of the observed universe of protein structures? Using information-theoretic inference, we answer this question with a dictionary of 1,493 substructures—called concepts—typically at a subdomain level, based on an unbiased subset of known protein structures. Each concept represents a topologically conserved assembly of helices and strands that make contact. Any protein structure can be dissected into instances of concepts from this dictionary. We dissected the Protein Data Bank and completely inventoried all the concept instances. This yields many insights, including correlations between concepts and catalytic activities or binding sites, useful for rational drug design; local amino-acid sequence–structure correlations, useful for ab initio structure prediction methods; and information supporting the recognition and exploration of evolutionary relationships, useful for structural studies. An interactive site, Proçodic, at http://lcb.infotech.monash.edu.au/prosodic (click), provides access to and navigation of the entire dictionary of concepts and their usages, and all associated information. This report is part of a continuing programme with the goal of elucidating fundamental principles of protein architecture, in the spirit of the work of Cyrus Chothia.
Highlights
The polypeptide chains of amino acids contain, in most proteins, regions that fold into helices and strands of sheets, which in turn assemble to give proteins their intricate three-dimensional shapes and folding patterns
This work uses the concise tableau representation of protein folding patterns introduced by Lesk (1995), which is based on the idea that the essence of a protein folding topology is captured by the order, patterns of contacts, and geometry of the assembly of secondary structural elements along the amino-acid chain
We have constructed the dictionary reported here using our recently developed method to infer, automatically, conserved assemblies of secondary structural elements within any given source collection of tableaux (Subramanian et al, 2017). We call these substructures concepts. This idea of a concept is constrained by the requirement that every secondary structural element in the concept must be in contact with at least one other secondarystructure element in that concept
Summary
The polypeptide chains of amino acids (primary structure) contain, in most proteins, regions that fold into helices and strands of sheets (secondary structure), which in turn assemble to give proteins their intricate three-dimensional shapes and folding patterns (tertiary and quaternary structures). As of April 2021, experimental methods have already provided more than 167,000 entries in the Protein Data Bank (PDB) (Berman et al, 2003), containing the three-dimensional coordinates of proteins and protein–nucleic acid complexes from a wide range of species. Unraveling protein architecture and discovering the relationship among these major levels of structural description provide the key to understanding how proteins function, how their 3D folding patterns form, and how they evolve (Lesk, 2016). Investigations of protein folding patterns have revealed recurrent themes (Pauling and Corey, 1951; Pauling et al, 1951; Levitt and Chothia, 1976; Lesk and Rose, 1981; Chothia and Lesk, 1986; Richards and Kundrot, 1988), which form the basis for widely used hierarchical classifications of protein structures (Murzin et al, 1995; Orengo et al, 1997; Andreeva et al, 2013; Schaeffer et al, 2016). François Jacob observed that proteins evolve by “bricolage,” that is, through evolutionary tinkering by reusing “pieces” from other proteins
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