MOLECULAR SKINS - A NEW CONCEPT FOR QUANTITATIVE SHAPE-MATCHING OF A PROTEIN WITH ITS SMALL-MOLECULE MIMICS

A novel analytical method for comparing molecular shapes by optimizing the intersection of molecular ''SKINS'' has been developed. This meth od provides a quantitative measure of the shape similarity by maximizi ng the intersection volume of molecular surfaces with a finite thickne ss; a molecular skin. We report shape matching of a small tripeptide i nhibitor (DFKi) of elastase class proteins with the 56 residue turkey ovomucoid inhibitor (TOMI). To match a large elastase inhibitor such a s TOMI with a small inhibitor or drug, we found that it is necessary t o use a skin match rather than molecular volume. Skin based comparison s of TOMI protein with DFKi successfully found the alignment expected from comparison of their respective crystallographic complexes with el astase (i.e. HLE/TOMI complex and PPE/tripeptide complex). In the skin comparison of the tripeptide with the TOMI protein, blind searching f or skin matches involved optimization of the skin intersection from 17 2 starting positions randomly selected from a set of 500 points on the TOMI van der Waals surface [within 9.5 angstrom of the Leu-18 on the TOMI binding loop (1 point/angstrom2)]. The tripeptide center of mass was placed at these points and its orientation was randomized before o ptimization was initiated. The best skin intersection, 86.4 angstrom3, was found three times and corresponds to the experimental alignment. The next best skin intersection was 78.1 angstrom3 giving a discrimina tion factor in this case of 10%. Searches over the entire surface of t he TOMI protein did not identify any new matches with skin intersectio n greater than 78.1 angstrom3. Matching the DFKi with a TOMI structure relaxed from its crystal conformation by molecular dynamics gives sim ilar results. (C) 1993 Wiley-Liss, Inc.