Practical Guide to Homology Modeling: Difference between revisions
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Even when the sequence alignment and template result in a correct backbone fold for the homology model, the sidechain rotamer positions will be incorrect. Despite knowing where each alpha carbon atom is located, theory does not correctly predict how the sidechains will fit together. At best, the sidechain rotamer positions will avoid steric clashes and electrostatic repulsions of like charges, and may optimize some salt bridges and hydrogen bonds. However, when a high quality empirical model becomes available, the details of sidechain packing in the homology model will be shown to be incorrect. | Even when the sequence alignment and template result in a correct backbone fold for the homology model, the sidechain rotamer positions will be incorrect. Despite knowing where each alpha carbon atom is located, theory does not correctly predict how the sidechains will fit together. At best, the sidechain rotamer positions will avoid steric clashes and electrostatic repulsions of like charges, and may optimize some salt bridges and hydrogen bonds. However, when a high quality empirical model becomes available, the details of sidechain packing in the homology model will be shown to be incorrect. | ||
==Strengths of Homology Models== | |||
Given the limitations explained above, you might well wonder whether homology models have any uses. Provided that the sequence alignment is reliable (35% identity or more), the backbone fold is likely to be correct. This provides a great deal of information despite the inaccuracies in sidechain positions. | |||
*The model indicates which residues are on the '''surface''' and which are '''buried'''. | |||
*If mutagenesis studies have shown phenotypic changes, it will be useful to see where the crucial residues lie in the homology model. | |||
*The distribution of evolutionarily conserved residues may suggest functional sites. For example, coloring the homology model by evolutionary conservation (e.g. with the [[ConSurf Server]]) may show '''patches or pockets of highly conserved residues'''. Pay attention to which residues may be missing from the homology model for the reasons explained above. Some missing residues could be highly conserved. | |||
The distribution of '''charges''' on the surface may be useful. For example, a large region or pocket with exclusively positive charges may be a binding site for nucleotides, DNA or RNA. A region devoid of charges suggests interaction with something hydrophobic<ref>Lipases commonly have a hydrophobic surface (devoid of charges) around their active sites. See [[Lipase lid morph]].</ref>Remember that the fine details of charge distribution will be incorrect; however the general arrangement may be informative. Also pay attention to whether some charged residues are missing in the model, as explained above, due to gaps in the sequence alignment or missing residues in the template. [[FirstGlance in Jmol]] quantitates missing charges. | |||
== References == | == References == | ||
<references/> | <references/> | ||
