Modeling homology

One of the ultimate goals of protein modeling is the prediction of 3D structures of proteins from their amino acid sequences. The prediction of protein structures rely on two approaches that are complementary and can be used in conjunction with each other  

Knowledge-based model combining sequence data to other information, such as homology modeling (Hilbert et al, 1993 Chinea et al, 1995). 

Energy-based calculations through theoretical models and energy minimization, such as ab initio prediction (Bonneau and Baker, 2001). 

Start from the known sequences and align the sequences of the target and the protein or proteins of known structure. Often the InDels (insertions and deletions) between the related structures occur in the loop regions between a-helices and p-strands. 

Assemble fragments/substructures from different, known homologous structures. Overlapping the main-chains of the target protein and the structure of the closely related protein of known structure. 

1 Entzeroth, M. (2003) Emerging trends in high-throughput screening. Current Opinion in Pharmacology, 3, 522-529. 

4 Kontoyianni, M., Madhav, P., Suchanek, E., and Seibel, W. (2008) Theoretical and practical considerations in virtual screening a beaten field Current Medicinal Chemistry, 15, 107—116. 

5 Cavasotto, C.N. and Orry A.J. (2007) Ligand docking and structure-based virtual screening in drug discovery. Current Topics in Medicinal Chemistry, 7, 1006-1014. 

6 Kitchen, D.B., Decornez, H., Furr, J.R., and Bajorath, J. (2004) Docking and scoring in virtual screening for drug discovery methods and applications. Nature Reviews. Drug Discovery, 3, 935-949. 

7 Lundstrom, K (2007) Structuralgenomics and drug discovery. Journal of Cellular and Molecular Medicine, 11, 224-238. 

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Homology modeling is discnssed in recent computational drug design texts and... 

TF Flavel. Predicting the structure of the fiavodoxm from Eschericia coli by homology modeling, distance geometry and molecular dynamics. Mol Simul 10 175-210, 1993. 

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. 

P Koehl, M Delame. A self consistent mean field approach to simultaneous gap closure and side-chain positioning m protein homology modelling. Nature Struct Biol 2 163-170, 1995. R Samudrala, J Moult. A graph-theoretic algorithm for comparative modeling of protein structure. J Mol Biol 279 287-302, 1998. 

MJ Bower, FE Cohen, RL Dunbrack Jr. Prediction of protein side-chain rotamers from a backbone-dependent rotamer library A new homology modeling tool. J Mol Biol 267 1268-1282, 1997. 

C Lee. Testing homology modeling on mutant proteins Pi edictmg stiaictural and thermodynamic effects m the Ala98 Val mutants of T4 lysozyme. Folding Des 1 1-12, 1995. 

D Cregut, J-P Liautard, L Chiche. Homology modeling of annexm I Implicit solvation improves side-chain prediction and combination of evaluation criteria allows recognition of different types of conformational eiTor. Protein Eng 7 1333-1344, 1994. 

S Modi, MI Paine, MI Sutcliffe, L-Y Lian, WU Pnmi-ose, CR Wolfe, GCK Roberts. A model for human cytochrome P450 2d6 based on homology modeling and NMR studies of substrate binding. Biochemistry 35 4540-4550, 1996. 

Aszodi, A., Taylor, W.R. Homology modelling by distance geometry. Fold. Des. 1 325-334, 1996. 

Three-dimensional models can be obtained most easily if the 3D structure of a homologous protein is known (homology modelling, comparative modelling). A homology model can only be as good as the sequence... 

More detailed aspects of protein function can be obtained also by force-field based approaches. Whereas protein function requires protein dynamics, no experimental technique can observe it directly on an atomic scale, and motions have to be simulated by molecular dynamics (MD) simulations. Also free energy differences (e.g. between binding energies of different protein ligands) can be characterised by MD simulations. Molecular mechanics or molecular dynamics based approaches are also necessary for homology modelling and for structure refinement in X-ray crystallography and NMR structure determination. 

The aim of the second dimension depth is to consider protein 3D-stmctures to uncover structure-function relationships. Starting from the protein sequences, the steps in the depth dimension are structure prediction, homology modeling of protein structures, and the simulation of protein-protein interactions and ligand-complexes. 

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. 

Predicting a likely conformation or fold of a particular region of a protein with less or no sequence similarity to protein structures recorded in the PDB, is the main challenges for homology modeling of proteins. 

HMG CoA-Reductase HMG-CoA-Reductase Inhibitors Homologous Desensitization Homologous Proteins Homologous Recombination Homology Modeling Hormonal Contraceptives Hormone Replacement Therapy (HRT)... 

The initial results of an early directed evolution study are all the more significant, because no X-ray data or homology models were available then to serve as a possible guide [89]. In a model study using whole E. coU cells containing the CHMO from Adnetohacter sp. NCIM B9871,4-hydroxy-cydohexanone (3 5) was used as the substrate. The WT leads to the preferential formation of the primary product (i )-36, which spontaneously rearranges to the thermodynamically more stable lactone (R)-37. The enantiomeric excess of this desymmetrization is only 9%, and the sense of enantioselectivity (R) is opposite to the usually observed (S)-preference displayed by simple 4-alkyl-substituted cydohexanone derivatives (see Scheme 2.10) [84—87]. 

Wang S-Q, Du Q-S, Chou K-C (2007) Study of drug resistance of chicken influenza A virus (H5N1) from homology-modeled 3D structures of neuraminidases. Biochem Biophys Res Commun 354 634-640... 

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