The probable conformation of substrates recognized by dipeptidyl-peptidase IV and some aspects of the catalytic mechanism derived from theoretical investigations.

By theoretical conformational investigations of substrates and nonsubstrates of the enzyme dipeptidyl-peptidase IV (DP IV) as well as dipeptide-esters using the ECEPP83 method we determined the structure of peptides recognized and cleaved by the enzyme. From a comparison of all possible structures for the substrates with conformations not possible in nonsubstrates we concluded that a single conformation explains substrate specificities of DP IV. This conformation is characterized by the following dihedral angles: psi 1 = 85 degrees, omega 1 = 180 degrees, phi 2 = -75 degrees, psi 2 = 80 degrees, and omega 2 = 180 degrees. The conclusions were supported by comparisons of molecular electrostatic potentials calculated with the molecular graphics program HAMOG.