A reduced amino acid alphabet for understanding and designing protein adaptation to mutation

Abstract

Protein sequence world is considerably larger than structure world. In consequence, numerous non-related sequences may adopt similar 3D folds and different kinds of amino acids may thus be found in similar 3D structures. By grouping together the 20 amino acids into a smaller number of representative residues with similar features, sequence world simplification may be achieved. This clustering hence defines a reduced amino acid alphabet (reduced AAA). Numerous works have shown that protein 3D structures are composed of a limited number of building blocks, defining a structural alphabet. We previously identified such an alphabet composed of 16 representative structural motifs (5-residues length) called Protein Blocks (PBs). This alphabet permits to translate the structure (3D) in sequence of PBs (1D). Based on these two concepts, reduced AAA and PBs, we analyzed the distributions of the different kinds of amino acids and their equivalences in the structural context. Different reduced sets were considered. Recurrent amino acid associations were found in all the local structures while other were specific of some local structures (PBs) (e.g Cysteine, Histidine, Threonine and Serine for the alpha-helix Ncap). Some similar associations are found in other reduced AAAs, e.g Ile with Val, or hydrophobic aromatic residues Trp with Phe and Tyr. We put into evidence interesting alternative associations. This highlights the dependence on the information considered (sequence or structure). This approach, equivalent to a substitution matrix, could be useful for designing protein sequence with different features (for instance adaptation to environment) while preserving mainly the 3D fold.

Analysis of protein contacts into Protein Units

“…computed from distance between the amino acids using the Euclidean distance between the amino acid vectors. Similar approaches have been applied to Protein Blocks in a recent study [89]. We found that, with the increase of R values, amino acid composition of PUs deviated more and more from the average composition of proteins.…”

“…Protein Blocks (PBs) correspond to a set of 16 local prototypes [54,56,[85][86][87][88][89], labeled from a to p, of 5 residues length based on , dihedral angles description [90]. They were obtained by an unsupervised classifier similar to Kohonen Maps [91,92] and Hidden Markov Models [93].…”

Protein contacts, inter-residue interactions and side-chain modelling

“…only 22% of the contacts of SC 4 are considered by C 8 . As we showed with reduced amino acid alphabets, the use of different definitions could lead to diverging results [123]. Distribution of the privileged interactions shows expected results, like the importance of Cysteine and of aromatic residues [105,106,[124][125][126][127][128][129][130].…”

Protein short loop prediction in terms of a structural alphabet

“…They have been used both to describe the 3D protein backbones ( ) and to perform a local de Brevern et al, 2000de Brevern, 2005 structure prediction ( ; ; ; ; de Brevern et al, 2000de Brevern et al, 2004Dong et al, 2008Etchebest et al, 2005. PBs have proven their efficiency in the description and the prediction of long fragments ( ;Hansmann, 2008Benros et al, 2009;;;), to compare protein al., 2006de Brevern and Hazout, 2003de Brevern et al, 2002;), to build globular ( ) and transmembrane protein Tyagi et al, 2008Tyagi et al, 2006aTyagi et al, 2006bDong et al, 2007;), to define a reduced amino acid alphabet dedicated to de Brevern et al, 2005 mutation design ( ), to design peptides ( ), to define binding site signatures ( Etchebest et al, 2007Thomas et al, 2006Dudev and Lim, 2007 or to analyze protein contacts ( ). The features of this alphabet have been compared with those of 8 other structural Faure et al, 2009 alphabets showing clearly that our PB alphabet is highly informative, with the best predictive ability of those tested ( ).…”