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Covariance analysis of protein families: The case of the variable domains of antibodies
Author(s) -
Choulier Laurence,
Lafont Virginie,
Hugo Nicolas,
Altschuh Danièle
Publication year - 2000
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/1097-0134(20001201)41:4<475::aid-prot50>3.0.co;2-g
Subject(s) - covariance , covariant transformation , variable (mathematics) , computational biology , genetics , protein structure , function (biology) , sequence (biology) , mathematics , biology , statistics , biochemistry , geometry , mathematical analysis
A nonrestrictive method for identifying covariance in protein families is described and applied to human and mouse germline Vκ and VH sequence alignments. Amino acids that occur at each position in a sequence alignment are divided into two sets, called a word , by generating all possible combinations of alternative amino acids. Each word is associated with a pattern of changes. Words with identical patterns identify covariant positions. In antibody variable domains, the number of words generated ranged between 1103 and 2195 depending on the alignment, of which 4 to 12 % occurred in covariant pairs. Despite the nonrestrictive character of pattern generation, covariant residues did not reflect a random selection with respect to the nature of amino acid changes and/or their spatial proximity in a reference crystallographic structure. This approach allowed the identification of a covariance signal for positions with high variability, mostly located in the outer part of the common structural framework of antibody variable domains. Covariance in these regions may reflect the existence of alternative and mutually exclusive atomic arrangements that are compatible with antibody function. The method may be of general applicability to rationalize residue variability in protein families. Proteins 2000;41:475–484. © 2000 Wiley‐Liss, Inc.