Energy strain in three-dimensional protein structures.

BACKGROUND Steric strain in protein three-dimensional structures is related to unfavorable inter-atomic interactions. The steric strain may be a result of packing or functional requirements, or may indicate an error in the coordinates of a structure. Detailed energy functions are, however, usually considered too noisy for error detection. RESULTS After a short energy refinement, a full-atom, detailed energy function becomes a sensitive indicator of errors. The statistics of the energy distribution of amino acid residues in high-resolution crystal structures, represented by models with idealized covalent geometry, were calculated. The interaction energy of each residue with the whole protein structure and with the solvent was considered. Normalized deviations of amino acid residue energies from their average values were used for detecting energy-strained and, therefore, potentially incorrect fragments of a polypeptide chain. Protein three-dimensional structures of different origin (X-ray crystallography, NMR spectroscopy, theoretical models and deliberately misfolded decoys) were compared. Examples of the applications to loop and homology modeling are provided. CONCLUSIONS Elevated levels of energy strain may point at a problematic fragment in a protein three-dimensional structure of either experimental or theoretical origin. The approach may be useful in model building and refinement, modeling by homology, protein design, folding calculations, and protein structure analysis.