Structural conservation in single-domain proteins: Implications for homology modeling

Large-scale sequencing projects are widening the gap between the known prot ein universe and the fraction for which structural information has been exp erimentally obtained. Through the application of homology (comparative) mod eling and more general structure prediction techniques, this gap can, howev er, be narrowed, providing indirect structural information for a considerab le number of proteins. Moreover, the estimated number of existing protein f olds seems to be limited and many of these yet unknown folds should be disc overed by dedicated large-scale structural genomics projects. Within this p erspective, homology (comparative) modeling will gain in importance, as wil l the use of models derived by this technique. Here we discuss how well a s equence alignment, the most common starting point for generating a model, r eflects the structural conservation between homologous proteins and we show that sequence information is able to direct construction of acceptable mod els as far as the structural core is concerned. We also show here that the regions surrounding insertions and deletions are much less conserved than t he core and discuss the implications of this observation for loop modeling. (C) 2001 Academic Press.