Homology model building

MI Sutcliffe, CM Dobson, RE Oswald. Solution structure of neuronal bungarotoxm determined by two-dimensional NMR spectroscopy Calculation of tertiary structure using systematic homologous model building, dynamical simulated annealing, and restrained molecular dynamics. Biochemistry 31 2962-2970, 1992. 

In the protein structure database PDB ( http //www. rcsb.org/pdb), by X-ray crystallography and NMR spectroscopy, experimentally solved 3D-protein structures are available to the public. Homology model building for a query sequence uses protein portions of known 3D-stmctures as structural templates for proteins with high sequence similarity. 

Koymans LMH, Vermeulen NPE, Baarslag A, Donne-Op den Kelder GM. A preliminary 3D model for cytochrome P450 2D6 constructed by homology model building. J Comput-Aided Mol Des 1993 7 281-9. 

A simplified flow chart for homology model building... 

Figure 3 Development of the number of new crystal structures and homology models published over the years. The overall steady increase is clearly visible, as is the increase in homology and pharmacophore models during (temporary) declines in number of crystal structures, illustrating the complementary nature of experimental structure determination and model building. Publication of structures for isoforms that have been extensively used for homology model building are indicated at the top.

As shown in Table 1, the trend in CYP homology model building is clearly toward a multi-integrated approach using multiple sequence alignments (multiple), structural alignments in combination with mutational, spectroscopic and enzyme kinetic experimental data and new or available pharmacophore models,... 

For peptides and nucleic acids, the system should provide rapid generation of a model from sequence data in any of the commonly observed conformations (e.g., a-helix, /J-sheet, /2-turn, B-DNA, Z-DNA). For peptides, it should be possible to make insertions or deletions in the sequence easily and to mutate side chains for homology model-building applications, where the sequence of the unknown structure is mapped onto the three-dimensional structure of a sequentially homologous protein whose structure has previously been determined by X-ray crystallography. 

The most robust of the structure prediction techniques is homology model building or threading (Bryant and Lawrence, 1993 Fetrow and Bryant, 1993 Jones and Thornton, 1996). The threading methods search for structures that have a similar... 

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