Structural Characteristics of Novel Protein Folds

Abstract

Folds are the basic building blocks of protein structures. Understanding the emergence of novel protein folds is an important step towards understanding the rules governing the evolution of protein structure and function and for developing tools for protein structure modeling and design. We explored the frequency of occurrences of an exhaustively classified library of supersecondary structural elements (Smotifs), in protein structures, in order to identify features that would define a fold as novel compared to previously known structures. We found that a surprisingly small set of Smotifs is sufficient to describe all known folds. Furthermore, novel folds do not require novel Smotifs, but rather are a new combination of existing ones. Novel folds can be typified by the inclusion of a relatively higher number of rarely occurring Smotifs in their structures and, to a lesser extent, by a novel topological combination of commonly occurring Smotifs. When investigating the structural features of Smotifs, we found that the top 10% of most frequent ones have a higher fraction of internal contacts, while some of the most rare motifs are larger, and contain a longer loop region.

Frag’r’Us: knowledge-based sampling of protein backbone conformations for de novo structure-based protein design

“…Furthermore, we described that the dramatic increase of structures in the protein databank has resulted in the saturation of sampling of loop structures, even in the case of long loops (Bonet et al, 2014;Fernandez-Fuentes and Fiser, 2006) subsequently confirmed (Choi and Deane, 2010), and that the geometry of smotifs is fully sampled (Fernandez-Fuentes et al, 2010).…”

Smotifs as structural local descriptors of supersecondary elements: classification, completeness and applications

“…We presented our results in the automatic structural classification of loops [30][31][32][33][34][35] and how this information can be used to predict the structure of protein loops [33,36,37]. We also discussed the limitations of the methodology [38,39]. Finally, we described how our loop classification could be applied to protein structure prediction using a hybrid ab initio approach [40] and de novo structure-based protein design [41].…”

Tertiary alphabet for the observable protein structural universe

“…Reductionist representations of protein structure have been of long-standing interest (1), with many studies having shown degeneracy at various structural levels (2)(3)(4)(5). Features ranging from backbone or side-chain dihedral angles (6,7) to domains and folds (8,9) have been classified, and structural basins of attraction have been found in select motifs (10)(11)(12)(13)(14)(15)(16)(17), offering a glimpse of a modular space with frequently repeating elements. The reason behind this modularity appears to be a combination of evolutionary history and the fundamental physics of structure.…”

“…Degeneracy at the secondary and supersecondary structural levels has been well studied (2,3,16), with emergent insights greatly benefiting protein design and structure prediction applications (4,5,(25)(26)(27)(28)(29)(30). Much work has focused on clustering short contiguous backbone fragments of fixed length (5,(31)(32)(33)(34).…”

“…A more recent analysis by Fiser and coworkers (16) classified all instances of two consecutive regular secondary-structural elements (SSEs) connected by a loop based on four parameters defining the relative orientation of the two SSEs, showing considerable degeneracy and saturation of the Protein Data Bank (PDB). The library of these motifs (Smotifs) has been used in loop and structure prediction (28,29).…”