Abstract
BackgroundProtein sequence alignments and database search methods use standard scoring matrices calculated from amino acid substitution frequencies in general sets of proteins. These general-purpose matrices are not optimal to align accurately sequences with marked compositional biases, such as hydrophobic transmembrane regions found in membrane proteins. In this work, an amino acid substitution matrix (GPCRtm) is calculated for the membrane spanning segments of the G protein-coupled receptor (GPCR) rhodopsin family; one of the largest transmembrane protein family in humans with great importance in health and disease.ResultsThe GPCRtm matrix reveals the amino acid compositional bias distinctive of the GPCR rhodopsin family and differs from other standard substitution matrices. These membrane receptors, as expected, are characterized by a high content of hydrophobic residues with regard to globular proteins. On the other hand, the presence of polar and charged residues is higher than in average membrane proteins, displaying high frequencies of replacement within themselves.ConclusionsAnalysis of amino acid frequencies and values obtained from the GPCRtm matrix reveals patterns of residue replacements different from other standard substitution matrices. GPCRs prioritize the reactivity properties of the amino acids over their bulkiness in the transmembrane regions. A distinctive role is that charged and polar residues seem to evolve at different rates than other amino acids. This observation is related to the role of the transmembrane bundle in the binding of ligands, that in many cases involve electrostatic and hydrogen bond interactions. This new matrix can be useful in database search and for the construction of more accurate sequence alignments of GPCRs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0639-4) contains supplementary material, which is available to authorized users.
Highlights
Protein sequence alignments and database search methods use standard scoring matrices calculated from amino acid substitution frequencies in general sets of proteins
Amino acid compositional bias in the rhodopsin family of G protein-coupled receptor (GPCR) The average amino acid composition of the TM regions of the rhodopsin family was compared with amino acid frequencies derived from other studies (Table 1)
The fraction of hydrophobic residues in the membrane spanning regions of GPCRs is similar to other TM proteins (JTTtm and PHDhtm) and is higher than in general proteins (BLOSUM62, and Swiss-Prot)
Summary
Protein sequence alignments and database search methods use standard scoring matrices calculated from amino acid substitution frequencies in general sets of proteins. Amino acid substitution matrices are obtained by the application of statistical methods on sequence alignments of evolutionarily related proteins (generally globular) and in all cases are biased by the composition of the data set used [18]. In this regard, it is known that the evolutionary selective pressure that governs the conservation and relative mutability of amino acids varies among protein families. These matrices, in many cases have proven to be more effective than the standard matrices in recognizing evolutionary relationships between the proteins of interest
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