Homology Modeling

Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein (the "template"). Homology modeling relies on the identification of one or more known protein structures likely to resemble the structure of the query sequence, and on the production of an alignment that maps residues in the query sequence to residues in the template sequence. It has been shown that protein structures are more conserved than protein sequences amongst homologues, but sequences falling below a 20% sequence identity can have very different structure.

Evolutionarily related proteins have similar sequences and naturally occurring homologous proteins have similar protein structure. It has been shown that three-dimensional protein structure is evolutionarily more conserved than would be expected on the basis of sequence conservation alone.

The sequence alignment and template structure are then used to produce a structural model of the target. Because protein structures are more conserved than DNA sequences, detectable levels of sequence similarity usually imply significant structural similarity.

The quality of the homology model is dependent on the quality of the sequence alignment and template structure. The approach can be complicated by the presence of alignment gaps (commonly called indels) that indicate a structural region present in the target but not in the template, and by structure gaps in the template that arise from poor resolution in the experimental procedure (usually X-ray crystallography) used to solve the structure. Model quality declines with decreasing sequence identity; a typical model has ~1–2 Å root mean square deviation between the matched Cα atoms at 70% sequence identity but only 2–4 Å agreement at 25% sequence identity. However, the errors are significantly higher in the loop regions, where the amino acid sequences of the target and template proteins may be completely different.

Regions of the model that were constructed without a template, usually by loop modeling, are generally much less accurate than the rest of the model. Errors in side chain packing and position also increase with decreasing identity, and variations in these packing configurations have been suggested as a major reason for poor model quality at low identity. Taken together, these various atomic-position errors are significant and impede the use of homology models for purposes that require atomic-resolution data, such as drug design and protein–protein interaction predictions; even the quaternary structure of a protein may be difficult to predict from homology models of its subunit(s). Nevertheless, homology models can be useful in reaching qualitative conclusions about the biochemistry of the query sequence, especially in formulating hypotheses about why certain residues are conserved, which may in turn lead to experiments to test those hypotheses. For example, the spatial arrangement of conserved residues may suggest whether a particular residue is conserved to stabilize the folding, to participate in binding some small molecule, or to foster association with another protein or nucleic acid.

Homology modeling can produce high-quality structural models when the target and template are closely related, which has inspired the formation of a structural genomics consortium dedicated to the production of representative experimental structures for all classes of protein folds. The chief inaccuracies in homology modeling, which worsen with lower sequence identity, derive from errors in the initial sequence alignment and from improper template selection. Like other methods of structure prediction, current practice in homology modeling is assessed in a biannual large-scale experiment known as the Critical Assessment of Techniques for Protein Structure Prediction, or CASP.

Read more about Homology Modeling:  Motive, Steps in Model Production, Template Selection and Sequence Alignment, Model Generation, Loop Modeling, Model Assessment, Benchmarking, Accuracy, Sources of Error, Utility

Other articles related to "modeling, homology modeling, homology":

Loop Modeling
... Loop modeling is a problem in protein structure prediction requiring the prediction of the conformations of loop regions in proteins with or without the use of a structural template ... The problem arises often in homology modeling, where the tertiary structure of an amino acid sequence is predicted based on a sequence alignment to a ... Consequently, they often cannot be modeled using standard homology modeling techniques ...
RAPTOR (software) - Comparison of Techniques - Protein Threading Vs. Homology Modeling
... If there is no homology found, the researcher must perform either X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, both of which require considerable time ... Protein threading is more effective than homology modeling, especially for proteins which have few homologs detectable by sequence alignment ... Unlike homology modeling, which selects template purely based on homology information (sequence alignments), the scoring function used in protein threading utilizes both ...
Homology Modeling - Utility
... Even low-accuracy homology models can be useful for these purposes, because their inaccuracies tend to be located in the loops on the protein surface, which are normally more variable even ... Homology models can also be used to identify subtle differences between related proteins that have not all been solved structurally ... Used in conjunction with molecular dynamics simulations, homology models can also generate hypotheses about the kinetics and dynamics of a protein, as ...

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