Use of a structural alphabet to find compatible folds for amino acid sequences

Abstract

The structural annotation of proteins with no detectable homologs of known 3D structure identified using sequence-search methods is a major challenge today. We propose an original method that computes the conditional probabilities for the amino-acid sequence of a protein to fit to known protein 3D structures using a structural alphabet, known as "Protein Blocks" (PBs). PBs constitute a library of 16 local structural prototypes that approximate every part of protein backbone structures. It is used to encode 3D protein structures into 1D PB sequences and to capture sequence to structure relationships. Our method relies on amino acid occurrence matrices, one for each PB, to score global and local threading of query amino acid sequences to protein folds encoded into PB sequences. It does not use any information from residue contacts or sequencesearch methods or explicit incorporation of hydrophobic effect. The performance of the method was assessed with independent test datasets derived from SCOP 1.75A. With a Z-score cutoff that achieved 95% specificity (i.e., less than 5% false positives), global and local threading showed sensitivity of 64.1% and 34.2%, respectively. We further tested its performance on 57 difficult CASP10 targets that had no known homologs in PDB: 38 compatible templates were identified by our Additional Supporting Information may be found in the online version of this article. approach and 66% of these hits yielded correctly predicted structures. This method scales-up well and offers promising perspectives for structural annotations at genomic level. It has been implemented in the form of a web-server that is freely available at http://www.bo-protscience.fr/forsa.

Discrete analyses of protein dynamics

“…The most recent impressive developments concern the inclusion of PBs in threading approaches (Mahajan, de Brevern, Sanejouand, Srinivasan & Offmann 2015;Vetrivel et al 2017) and fold recognition especially with ORION (Ghouzam, Postic, de Brevern & Gelly 2015;Ghouzam, Postic, Guerin, de Brevern & Gelly 2016).…”

Roadmap to the study of gene and protein phylogeny and evolution—A practical guide

“…I-TASSER [186], HHPred of the HH suite [187] and Alpha fold [188] can be used to predict the 3D structure of proteins from their aminoacid sequences. FoRSA [189] is able to identify a protein fold from its amino-acid sequence or a protein sequence in the proteome of a species from a crystal structure.…”

Structural variations within proteins can be as large as variations observed across their homologues

“…Protein Blocks are a 16 state classification of pentapeptide fragments that can abstract any part of a protein backbone structure [17][18] . The versatility of PBs to abstract protein structures have been exploited for diverse applications: to predict protein structure 19-21 , in fold recognition 22,23 , for structural motif identification [24][25][26] , molecular dynamics trajectory analysis 27,28 etc. 39 Furthermore,…”