Abstract
We have extracted an extensive collection of recurrent structural motifs (RSMs), which consist of sequentially non-contiguous structural motifs (4–6 residues), each of which appears with very similar conformation in three or more mutually unrelated protein structures. We find that the proteins in our set are covered to a substantial extent by the recurrent non-contiguous structural motifs, especially the helix and strand regions. Computational alanine scanning calculations indicate that the average folding free energy changes upon alanine mutation for most types of non-alanine residues are higher for amino acids that are present in recurrent structural motifs than for amino acids that are not. The non-alanine amino acids that are most common in the recurrent structural motifs, i.e., phenylalanine, isoleucine, leucine, valine and tyrosine and the less abundant methionine and tryptophan, have the largest folding free energy changes. This indicates that the recurrent structural motifs, as we define them, describe recurrent structural patterns that are important for protein stability. In view of their properties, such structural motifs are potentially useful for inter-residue contact prediction and protein structure refinement.
Highlights
The sequence of a protein largely determines its fold, but the folding process cannot realistically be achieved through an exhaustive exploration of the conformational space, and it is believed that proteins fold through a combination of local structural arrangements, such as helices and long range interactions that will lead to the formation of compact hydrophobic cores and/or sheets
Recurring patterns of structural arrangements of sequentially non-contiguous amino acids do represent frequently occurring and, thereby, statistically more likely inter-residue contacts, making them potentially useful for long-range contact-prediction, they have previously demonstrated themselves to be indicative of properties, such as binding affinity [32,33], catalytic activity [34,35], as well as intrinsic stability, as we have recently pointed out elsewhere [36]
Given the short discontinuous size of our motifs (4–6 residues) and the low overall sequence identity ensured between members of our motif set, we felt that any recurrent instances of strict conservation of our 4–6 residue motifs in other proteins should have interesting properties with respect to their intrinsic compactness/stability
Summary
The sequence of a protein largely determines its fold, but the folding process cannot realistically be achieved through an exhaustive exploration of the conformational space, and it is believed that proteins fold through a combination of local structural arrangements, such as helices and long range interactions that will lead to the formation of compact hydrophobic cores and/or sheets. In the protein structure prediction and protein modeling setting, Bowie and Eisenberg [6] pioneered the systematic use of sequentially contiguous fragments extracted from known experimentally determined structures to assemble new structures. Recurring patterns of structural arrangements of sequentially non-contiguous amino acids do represent frequently occurring and, thereby, statistically more likely inter-residue contacts, making them potentially useful for long-range contact-prediction, they have previously demonstrated themselves to be indicative of properties, such as binding affinity [32,33], catalytic activity [34,35], as well as intrinsic stability, as we have recently pointed out elsewhere [36]. The present collection of such patterns could prove to be a useful resource for protein structure modeling, protein structure refinement and a complement to the current flora of protein structure databases, which focus on sequentially contiguous fragments
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