Protein sequence model building

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. 

Further improvement of the map with these phases may reveal side chains more clearly. Now the trick is to identify some specific side chains so that the known amino-acid sequence of the protein can be aligned with visible features in the map. As mentioned earlier, chain termini are often ill-defined, so we need a foothold for alignment of sequence with map where the map is sharp. Many times the key is a short stretch of sequence containing several bulky hydrophobic residues, like Trp, Phe, and Tyr. Because they are hydro-phobic, they are likely to be in the interior where the map is clearer. Because they are bulky, their side-chain density is more likely to be identifiable. From such a foothold, the detailed model building can begin. 

The terms bioinformatics and cheminformatics refer to the use of computational methods in the study of biology and chemistry. Information from DNA or protein sequences, protein structure, and chemical structure is used to build models of biochemical systems or models of the interaction of a biochemical system with a small molecule (e.g., a drug). There are mathematical and statistical methods for analysis, public databases, and literature associated with each of these disciplines. However, there is substantial value in considering the interaction between these areas and in building computational models that integrate data from both sources. In the most... 

Fig. 1. Comparison of the three-dimensional structures of human Interleukin-8 (green) MCP-1 (blue) and Fractalkine (EST Z44443) (red). The 11-8 structure is taken from the Protein Database (PDB) entry (1IL8), and the MCP-1 structure is a model built of the NMR structure of MI P-l (> (PDB entry 1HUM). The intrachain disulfide bonds are shown in yellow. The model for the chemokine domain of Fractalkine was built using the SwissModel server (16,17). As can be seen the three structures show a large degree of conservation of the overall structure, despite a relatively low level of primary sequence identity. The additional three amino acids in Fractalkine are accommodated as a 310 helix between the two N-terminal cysteines. The steric requirements here presumably forbid a CX2C motif. The model building software can be accessed at http www.expasy.ch swissmod SWISS-MODEL.html...

Only compounds that show promise as possible ligands are actually prepared. On the other hand, if there is less information about the target available 1) a protein sequence and no characterized structure or 2) a set of compounds with different degrees of biological activity. Then the pharmacophoric model and hypothesis approach, discussed above, can be used. A 3-D pharmacophoric model building effort, using catalyst might develop pharmacophore models that can be used to search libraries of structures. 

For structures not determined by molecular replacement, the chemical sequence of the protein must be fit into the experimental electron density map (Figure 2.7). This is called model building or chain tracing. As one would expect, the success or failure of chain tracing is dependent upon the quality of the electron density map. Thus, map quality evaluation is very important before one attempts to trace the chain. Good (traceable) electron maps should display most of the following features. 

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