HOMOLOGY MODELING WITH INTERNAL COORDINATE MECHANICS - DEFORMATION ZONE MAPPING AND IMPROVEMENTS OF MODELS VIA CONFORMATIONAL SEARCH

Five models by homology containing insertions and deletions and rangin g from 33% to 48% sequence identity to the known homologue, and one hi gh sequence identity (85%) model were built for the CASP2 meeting, For all five low identity targets: (i) our starting models were improved by the Internal Coordinate Mechanics (ICM) energy optimization, (ii) t he refined models were consistently better than those built with the a utomatic SWISS-MODEL program, and (iii) the refined models differed by less than 2% from the best model submitted, as judged by the residue contact area difference (CAD) measure [Abagyan, R.A., Totrov, M.J. Mol . Biol. 268:678-685, 1997], The CAD measure is proposed for ranking mo dels built by homology instead of global root-mean-square deviation, w hich is frequently dominated by insignificant yet large contributions from incorrectly predicted fragments or side chains, We demonstrate th at the precise identification of regions of local backbone deviation i s an independent and crucial step in the homology modeling procedure a fter alignment, since aligned fragments can strongly deviate from the template at various distances from the alignment gap or even in the un gapped parts of the alignment, We show that a local alignment score ca n be used as an indicator of such local deviation, While four short lo ops of the meeting targets were predicted by database search, the best loop 1 from target T0028, for which the correct database fragment was not found, was predicted by Internal Coordinate Mechanics global ener gy optimization at 1.2 Angstrom accuracy, A classification scheme for errors in homology modeling is proposed. (C) 1998 Wiley-Liss,Inc.