Why not consider a spherical protein? Implications of backbone hydrogen bonding for protein structure and function

Abstract

Recent studies questioned whether the PDB contains all compact, single domain protein structures. Here, we show that all quasi-spherical, QS, random protein structures devoid of secondary structure are in the PDB and are excellent templates for all native PDB proteins up to 250 residues. Because QS templates have similar global contour as native, TASSER can refine 98% (90%) of those whose TM-score is 0.4 (0.35) to structures ≥ the 0.5 TM-score threshold (0.74 (0.64) mean TM-score) for CATH/SCOP assignment. Based on this and the fact that at a TM-score of 0.4, 83% (90%) of all (internal) core secondary structure elements are recovered, a 0.40 TM-score is an appropriate fold similarity assignment threshold. Despite claims of Taylor, Trovato and Zhou that many of their structures lack a PDB counterpart, using fr-TM-align, at a 0.45 (0.5) TM-score threshold, essentially all (most) are found in the PDB. Thus, the conclusion that the PDB is likely complete is further supported.

Interplay of physics and evolution in the likely origin of protein biochemical function

“…For a given polyleucine structure, a randomized sequence is generated based on the average amino acid composition in the PDB. The sequence is shuffled to give a low-energy structure for the ART structural template of interest (3). Then, the corresponding all-atom conformation is built from the Cα trace by Pulchra (41).…”

“…They offer the advantages of being comprehensive and could allow us to tease out which features of protein structures/sequences likely give rise to which functional properties. In earlier computational studies (3,4,(19)(20)(21), the ability of protein structures to exhibit some of the geometric features required for molecular function sans evolution was examined in three representative protein structure libraries: the PDB library, real, single domain protein structures found in the Protein Data Bank (22); the ART library, computationally generated, compact homopolypeptide, artificial, structures with protein-like secondary structure; and the QS library, quasi-spherical, random protein structures packed in the same average spherical volume as proteins but lacking backbone secondary structure and hydrogen bonding. Without evolutionary selection, the library of artificial structures has statistically significant structural matches to the global structures of native proteins and due to defects in packing secondary structural elements, native like pocket volumes.…”

“…How could the ability to bind ligands have arisen? Consider two extreme views: The "inherent functionality model" asserts that the ability to engage in such interactions is just a physical chemical property of proteins, with the formation of ligand-binding cavities arising from defects in the packing of secondary structural elements comprised of hydrophobic and hydrophilic residues (3,4), which evolution then exploits and amplifies. At the other extreme, in the "acquired functionality model," proteins were spherical objects without ligand-binding pockets.…”

The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation

“…Protein interfaces are usually large, with a buried solvent accessible area of over 1;000 Å 2 (3). With the exception of intertwined interface structures, most protein interfaces have planar shapes (4,9,10). Although there are in principle millions of ways of forming protein-protein interfaces, a recent study has revealed that the structural space of protein interfaces is surprisingly small, primarily attributed to limited ways of protein secondary structural packing and the flatness of interfaces (10).…”

“…Although very large ligands may be located on a more planar surface, to increase interaction strength, the majority of pockets are concave in shape so that they can firmly grasp or partially envelop their cognate ligands; hence, the name "pocket" (7,8). A very recent comparison between experimental and artificial quasispherical structures of single-domain proteins has proposed that packing by hydrogen-bonded secondary structures is crucial for the formation of protein interfaces and ligand-binding pockets (9).…”