title: Why not consider a spherical protein? Implications of backbone hydrogen bonding for protein structure and function.
abstract: The intrinsic ability of protein structures to exhibit the geometric features required for molecular function in the absence of evolution is examined in the context of three systems: the reference set of real, single domain protein structures, a library of computationally generated, compact homopolypeptides, artificial structures with protein-like secondary structural elements, and quasi-spherical random proteins packed at the same density as proteins but lacking backbone secondary structure and hydrogen bonding. Without any evolutionary selection, the library of artificial structures has similar backbone hydrogen bonding, global shape, surface to volume ratio and statistically significant structural matches to real protein global structures. Moreover, these artificial structures have native like ligand binding cavities, and a tiny subset has interfacial geometries consistent with native-like protein-protein interactions and DNA binding. In contrast, the quasi-spherical random proteins, being devoid of secondary structure, have a lower surface to volume ratio and lack ligand binding pockets and intermolecular interaction interfaces. Surprisingly, these quasi-spherical random proteins exhibit protein like distributions of virtual bond angles and almost all have a statistically significant structural match to real protein structures. This implies that it is local chain stiffness, even without backbone hydrogen bonding, and compactness that give rise to the likely completeness of the library solved single domain protein structures. These studies also suggest that the packing of secondary structural elements generates the requisite geometry for intermolecular binding. Thus, backbone hydrogen bonding plays an important role not only in protein structure but also in protein function. Such ability to bind biological molecules is an inherent feature of protein structure; if combined with appropriate protein sequences, it could provide the non-zero background probability for low-level function that evolution requires for selection to occur.
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St NW, Atlanta, GA 30076, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Brylinski
authors.forename: Mu
authors.initials: M
authors.lastname: Gao
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skolnick
mesh_terms: D000818:Animals; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D030562:Databases, Protein; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011506:Proteins; D004247:DNA