On the origin and highly likely completeness of single-domain protein structures

Abstract

The size and origin of the protein fold universe is of fundamental and practical importance. Analyzing randomly generated, compact sticky homopolypeptide conformations constructed in generic simplified and all-atom protein models, all have similar folds in the library of solved structures, the Protein Data Bank, and conversely, all compact, single-domain protein structures in the Protein Data Bank have structural analogues in the compact model set. Thus, both sets are highly likely complete, with the protein fold universe arising from compact conformations of hydrogen-bonded, secondary structures. Because side chains are represented by their C ␤ atoms, these results also suggest that the observed protein folds are insensitive to the details of side-chain packing. Sequence specificity enters both in fine-tuning the structure and thermodynamically stabilizing a given fold with respect to the set of alternatives. Scanning the models against a three-dimensional active-site library, close geometric matches are frequently found. Thus, the presence of active-site-like geometries also seems to be a consequence of the packing of compact, secondary structural elements. These results have significant implications for the evolution of protein structure and function.evolution ͉ Protein Data Bank ͉ protein folding ͉ protein structure prediction P rotein structures represent very interesting systems in that they result from both physical chemical principles (1) and the evolutionary selection for protein function (2). Focusing on the tertiary structures adopted by protein domains (roughly defined as independent folding units) (3), a number of key questions must be addressed. How large is the protein fold universe (4-6)? Is it essentially infinite, or is there a limited repertoire of single-domain topologies such that at some point, the library of solved protein structures in the Protein Data Bank (PDB) (7) would be sufficiently complete that the likelihood of finding a new fold is minimal? If the number of folds is finite, how complete is the current PDB library (6,8,9)? That is, how likely is it that a given protein, whose structure is currently unknown, will have an already-solved structural analogue? The answer to these questions is not only of intrinsic interest, but has practical applications to structural genomics target selection strategies (5, 10). More generally, can the set of protein folds and its degree of completeness be understood on the basis of general physical chemical principles, or is it very dependent on the details of protein stereochemistry and evolutionary history (11)?In recent work that builds on the other studies (8, 12, 13), we suggested that the library of single-domain proteins already found in the PDB is essentially complete in the sense that single-domain PDB structures provide a set of structures from which any other single-domain protein can be modeled (9,14). By using sensitive structural alignment algorithms that assess the structural similarity of two protein structures, even when proteins be...

Biophysics of protein evolution and evolutionary protein biophysics

“…A more recent study using computational sampling of homopolypeptide conformations suggested further that the current repertoire of globular protein folds is nearly complete in its coverage of all physically possible compact folds [286]. However, studies by three other groups have found instead that the current fold repertoire represents only a small fraction of all possible folds [287 -289].…”

Structural space of protein–protein interfaces is degenerate, close to complete, and highly connected

“…Consistent with this notion, it was estimated that there are about 1,000 structural folds in protein domains (10). Recent studies suggest that the library of single-domain protein structures is likely complete, continuous, and above the percolation threshold, largely due to the packing of compact, hydrogen-bonded secondary structural elements (11)(12)(13). Because many structural properties of real proteins are reproduced by a library of compact, hydrogen-bonded homopolypeptide structures, evolution is not necessary to explain these features.…”

“…Second, it is known that physical constraints limit the total number of distinct structural folds for protein domains (9,12). Obviously, the same constraints may restrict the valid ways of packing pairs of proteins; this is the second reason for detecting structural similarity between unrelated interfaces.…”

The network of sequence flow between protein structures

“…Arguments were made that the PDB is indeed complete (22,23) with the current thousands of distinct folds. This argument further supports the creation of a comprehensive model of protein structure space and their sequence capacities and the progressive refinement of this model.…”