A novel approach is proposed for modeling of structurally variable regions in proteins. In this approach, a prerequisite sequence-structure alignment is examined for regions where the target sequence is not covered by the structural template. These regions, extended with a number of residues from adjacent stem regions, are submitted to fold recognition. The alignments produced by fold recognition are integrated into the initial alignment to create a multiple alignment where gaps in the main structural template are covered by local structural templates. This multiple alignment is used to create a protein model by existing protein modeling techniques.
Several alternative parameters are evaluated using a set of ten proteins. One set of parameters is selected and evaluated using another set of 31 proteins. The most promising result is for loop regions not located at the C- or N-terminal of a protein, where the method produces an average RMSD 12% lower than the loop modeling provided with the program MODELLER. This improvement is shown to be statistically significant.