Enriching the sequence substitution matrix by structural information

A fundamental step in homology modeling is the comparison of two protein sequences: a probe sequence with an unknown structure and function and a template sequence for which the structure and function are known. The detection of protein similarities relies on a substitution matrix that scores the proximity of the aligned amino acids. Sequence‐to‐sequence alignments use symmetric substitution matrices, whereas the threading protocols use asymmetric matrices, testing the fitness of the probe sequence into the structure of the template protein. We propose a linear combination of threading and sequence‐alignment scoring function, to produce a single (mixed) scoring table. By fitting a single parameter (which is the relative contribution of the BLOSUM 50 matrix and the threading energy table of THOM2) we obtain a significant increase in prediction capacity in the twilight zone of homology modeling (detecting sequences with