Addition of side chains to a known backbone with defined side-chain centroids

An automatic procedure is proposed for adding side chains to a protein backbone; it is based on optimization of a simplified energy function for peptide side chains, given its backbone and positions of side-chain centroids. The energy is expressed as a sum of the energies of interaction between side chains, and a harmonic penalty function accounting for the preservation of the positions of the C-alpha atoms and the side-chain centroids. The energy of side-chain interactions is calculated with the soft-sphere ECEPP/3 potential. A Monte Carlo search is carried out to explore all possible side-chain orientations within a fixed backbone and side-chain centroid positions. The initial, usually extended, side-chain conformations are taken directly from the ECEPP/3 database. The procedure was tested on six experimental (X-ray or NMR) structures: immunoglobulin binding protein (PDB code 1IGD, an alpha+beta-protein); transcription factor PML (PDB code 1BOR, a 49-104 fragment of the ring finger domain, predominantly beta-protein); bovine pancreatic trypsin inhibitor (crystal form II) (PDB code 1BPI, an alpha + beta-protein); the monomer of human deoxyhemoglobin (PDB code 1BZO, an alpha-helical structure); chain A of alcohol dehydrogenase from Drosophila lebanonensis (PDB code 1A4U); as well as on the 10-55 portion of the B domain of staphylococcal protein A (PDB code 1BDD). In all cases except 1BPI, the data for the algorithm (i.e. the backbone or C-alpha coordinates and the positions of side-chain centroids) were taken from the experimental structures. For protein A, the C-alpha coordinates and positions of side-chain centroids were also taken from the 1.9-Angstrom-resolution model predicted by the UNRES force field. In all comparisons with experimental structures, complete side-chain geometry was reconstructed with a root-mean-square (RMS) deviation of approximately 0.6-0.9 Angstrom from the heavy atoms when complete backbone and side-chain-centroid coordinates were used in reconstruction, or approximately 1.0 Angstrom when the C-alpha and centroid coordinates were used. (C) 2002 Elsevier Science B.V. All rights reserved.