Accuracy
The accuracy of the structures generated by homology modeling is highly dependent on the sequence identity between target and template. Above 50% sequence identity, models tend to be reliable, with only minor errors in side chain packing and rotameric state, and an overall RMSD between the modeled and the experimental structure falling around 1 Â. This error is comparable to the typical resolution of a structure solved by NMR. In the 30–50% identity range, errors can be more severe and are often located in loops. Below 30% identity, serious errors occur, sometimes resulting in the basic fold being mis-predicted. This low-identity region is often referred to as the "twilight zone" within which homology modeling is extremely difficult, and to which it is possibly less suited than fold recognition methods.
At high sequence identities, the primary source of error in homology modeling derives from the choice of the template or templates on which the model is based, while lower identities exhibit serious errors in sequence alignment that inhibit the production of high-quality models. It has been suggested that the major impediment to quality model production is inadequacies in sequence alignment, since "optimal" structural alignments between two proteins of known structure can be used as input to current modeling methods to produce quite accurate reproductions of the original experimental structure.
Attempts have been made to improve the accuracy of homology models built with existing methods by subjecting them to molecular dynamics simulation in an effort to improve their RMSD to the experimental structure. However, current force field parameterizations may not be sufficiently accurate for this task, since homology models used as starting structures for molecular dynamics tend to produce slightly worse structures. Slight improvements have been observed in cases where significant restraints were used during the simulation.
Read more about this topic: Homology Modeling
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