Open AccessKnowledge‐based protein modelling and design
Author(s) -
BLUNDELL Tom,
CARNEY Devon,
GARDNER Stephen,
HAYES Fiona,
HOWLIN Brendan,
HUBBARD Tim,
OVERINGTON John,
SINGH Diljeet Athwal,
SIBANDA Bancinyane Lynn,
SUTCLIFFE Michael
Publication year - 1988
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1988.tb13917.x
Subject(s) - protein superfamily , computational biology , homology (biology) , loop modeling , protein structure , protein tertiary structure , protein structure database , homology modeling , structural alignment , protein structure prediction , peptide sequence , biology , computer science , chemistry , sequence alignment , bioinformatics , amino acid , biochemistry , gene , sequence database , enzyme
A systematic technique for protein modelling that is applicable to the design of drugs, peptide vaccines and novel proteins is described. Our approach is knowledge‐based, depending on the structures of homologous or analogous proteins and more generally on a relational data base of protein three‐dimensional structures. The procedure simultaneously aligns the known tertiary structures, selects fragments from the structurally conserved regions on the basis of sequence homology, aligns these with the ‘average structure’ or ‘framework’, builds on the loops selected from homologous proteins or a wider database, substitutes sidechains and energy minimises the resultant model. Applications to modelling an homologous structure, tissue plasminogen activator on the basis of another serine proteinase, and to modelling an analogous protein, HIV viral proteinase on the basis of aspartic proteinases, are described. The converse problem of ab initio design is also addressed: this involves the selection of an amino acid sequence to give a particular tertiary structure, in this case a symmetrical domain of two Greek‐key motifs.