Protein homology modeling applications

Cavalli A, Greco G, Novellino E, Recanatini M. Linking CoMFA and protein homology models of enzyme-inhibitor interactions an application to nonsteroidal aromatase inhibitors. Bioorg Med Chem 2000 8 2771-80. 

The wide structural application of dipolar couplings is demonstrated by its use to validate models built by sequence homology methods. Additionally, dipolar couplings have been shown to reduce the RMSD between these models and the target structure. One example is the work reported by Chou et al., in which the RMSD of sequence homology models of the protein calmodulin, built from the structure of recoverin and parvalbumin, is reduced using heteronuclear dipolar couplings [110]. 

Application of PSSC is not limited to existing crystal structures of proteins. It could be applied to structures derived from homology models as well. A homology model, as applied for the 11 HSD types 1 and 2 enzymes performed well in the first application of PSSC for compound library design. Furthermore, it should be noted that the concept has not been developed to make predictions on structural complementarity or the appropriate orientation of functional groups in the binding site. 

This chapter focuses on the application of molecular modeling to calculate, manipulate, and predict protein structures and functions. Concepts of structure similarity/ overlap, homology modeling, and molecular docking, which are special concerns of protein biochemists, are considered. Approaches to protein modeling by the use of two programs (Swiss-Pdb Viewer and KineMage) and two online servers (B and CE) are described. 

Jean P, Pothier J, Dansette PM, et al. Automated multiple analysis of protein structures application to homology modeling of cytochromes P450. Proteins 1997 28 388-404. 

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. 

In many cases, for practical or technical reasons (as opposed to any fundamental physical reasons), the structures of protein complexes cannot be determined experimentally. If the structure of a protein complex with adequate sequence similarity is available, one can build the structure of a query complex by homology modeling [1-3]. The applicability of homology modeling to protein complexes is still limited because the current structural database provides only a sparse coverage of the protein interaction space. 

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