Model building sequence homology

Building sequence profiles or Hidden Markov Models to perform more sensitive homology searches. A sequence profile contains information about the variability of every sequence position, improving structure prediction methods (secondary structure prediction). Sequence profile searches have become readily available through the introduction of PsiBLAST [4]... 

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. 

If the sequence of a protein has more than 90% identity to a protein with known experimental 3D-stmcture, then it is an optimal case to build a homologous structural model based on that structural template. The margins of error for the model and for the experimental method are in similar ranges. The different amino acids have to be mutated virtually. The conformations of the new side chains can be derived either from residues of structurally characterized amino acids in a similar spatial environment or from side chain rotamer libraries for each amino acid type which are stored for different structural environments like beta-strands or alpha-helices. 

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,... 

The amino acid sequence of the enzyme is homologous with those of the pancreatic enzymes and has been shown by model building to be compatible with a chymotrypsin-like three-dimensional structure and catalytic site (36). The homology in sequence is particularly well marked around His-57. The enzyme s catalytic properties are virtually indistinguishable from those of pancreatic elastase. 

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