Abstract
It is much easier to determine a protein’s sequence than to determine its three dimensional structure and consequently homology modeling will be an essential aspect of most studies that require 3D protein structure data. Homology modeling templates tend to be PDB files. About 88% of all protein structures in the PDB have been determined with X-ray crystallography, and thus are based on crystals that by necessity hold non-natural packing contacts in accordance with the crystal symmetry. Active site residues, residues involved in intermolecular interactions, residues that get post-translationally modified, or other sites of interest, normally are located at the protein surface so that it is particularly important to correctly model surface-located residues. Unfortunately, surface residues are just those that suffer most from crystal packing artifacts. Our study of the influence of crystal packing artifacts on the quality of homology models reveals that this influence is much larger than generally assumed, and that the evaluation of the quality of homology models should properly account for these artifacts.
Highlights
Knowledge of the three dimensional structure of proteins is a prerequisite for rational drug design, for many forms of protein engineering, or for explaining the molecular phenotype associated with the disease phenotype caused by a mutation in the human genome
The numbers of wrongly modeled and correctly modeled residues were counted as function of the residue conservation and the presence of symmetry contacts in either the template or the real structure
The rationale is that the old WHAT IF modeling module puts great emphasis on the rotamericity of side chains [28,29], and, upon placing side chains does not know about symmetry contacts and should model all residues with a similar chance of success
Summary
Knowledge of the three dimensional structure of proteins is a prerequisite for rational drug design, for many forms of protein engineering, or for explaining the molecular phenotype associated with the disease phenotype caused by a mutation in the human genome. It is considerably easier to determine the sequence of a protein than it is to determine its structure, and homology modeling will be an essential aspect of most studies that require protein structure data. The homology modeling community is continuously working on improving all aspects of the process, and the bi-annual CASP ‘competition’ [1,2,3,4,5,6,7,8,9] is a good benchmark for where the field stands. The root mean square deviation of the atomic positions in a homology model from the equivalent atoms in the corresponding real structure after they have been optimally superposed is an important aspect of the evaluation of the quality of homology modeling procedures [10,11,12]. Other measures have been proposed [13,14,15,16,17,18,19]
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