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

Abstract

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 Cα 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 α+β-protein); transcription factor PML (PDB code 1BOR, a 49–104 fragment of the ring finger domain, predominantly β-protein); bovine pancreatic trypsin inhibitor (crystal form II) (PDB code 1BPI, an α+β-protein); the monomer of human deoxyhemoglobin (PDB code 1BZ0, an α-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 Cα coordinates and the positions of side-chain centroids) were taken from the experimental structures. For protein A, the Cα coordinates and positions of side-chain centroids were also taken from the 1.9-Å-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 Å from the heavy atoms when complete backbone and side-chain-centroid coordinates were used in reconstruction, or approximately 1.0 Å when the Cα and centroid coordinates were used.