MONSSTER - A METHOD FOR FOLDING GLOBULAR-PROTEINS WITH A SMALL NUMBEROF DISTANCE RESTRAINTS

The MONSSTER (MOdeling of New Structures from Secondary and TErtiary R estraints) method for folding of proteins using a small number of long -distance restraints (which can be up to seven times less than the tot al number of residues) and some knowledge of the secondary structure o f regular fragments is described. The method employs a high-coordinati on lattice representation of the protein chain that incorporates a var iety of potentials designed to produce protein-like behaviour. These i nclude statistical preferences for secondary structure, side-chain bur ial interactions, and a hydrogen-bond potential. Using this algorithm, several globular proteins (1ctf, 2gbl, 2trx, 3fxn, 1mba, 1pcy and 6pt i) have been folded to moderate-resolution, native-like compact states . For example, the 68 residue 1ctf molecule having ten loosely defined , long-range restraints was reproducibly obtained with a C-alpha-backb one root-mean-square deviation (RMSD) from native of about 4. Angstrom . Flavodoxin with 35 restraints has been folded to structures whose av erage RMSD is 4.28 Angstrom. Furthermore, using just 20 restraints, my oglobin, which is a 146 residue helical protein, has been folded to st ructures whose average RMSD from native is 5.65 Angstrom. Plastocyanin with 25 long-range restraints adopts conformations whose average RMSD is 5.44 Angstrom. Possible applications of the proposed approach to t he refinement of structures from NMR data, homology model-building and the determination of tertiary structure when the secondary structure and a small number of restraints are predicted are briefly discussed. (C) 1997 Academic Press Limited