SCREENING A PEPTIDYL DATABASE FOR POTENTIAL LIGANDS TO PROTEINS WITH SIDE-CHAIN FLEXIBILITY

The three key challenges addressed in our development of SPECITOPE, a tool for screening large structural databases for potential Ligands to a protein, are to eliminate infeasible candidates early in the search , incorporate Ligand and protein side-chain flexibility upon docking, and provide an appropriate rank. for potential new ligands. The protei n Ligand-binding site is modeled by a shell of surface atoms and by hy drogen-bonding template points for the Ligand to match, conferring spe cificity to the interaction. SPECITOPE combinatorially matches all hyd rogen-bond donors and accepters of the screened molecules to the templ ate points. By eliminating molecules that cannot match distance or hyd rogen-bond constraints, the transformation of potential docking candid ates into the ligand-binding site and the shape and hydrophobic comple mentarity evaluations are only required for a small subset of the data base. SPECITOPE screens 140,000 peptide fragments in about an hour and has identified and docked known inhibitors and potential new ligands to the free structures of four distinct targets: a serine protease, a DNA repair enzyme, an aspartic proteinase, and a glycosyltransferase. For all four, protein sidechain rotations were critical for successful docking, emphasizing the importance of inducible complementarity for accurately modeling ligand interactions. SPECITOPE has a range of pote ntial applications for understanding and engineering protein recogniti on, fi om inhibitor and linker design to protein docking and macromole cular assembly. (C) 1998 Wiley-Liss, Inc.