Homology modelling

Due to the improving experimental techniques, the protein stracture deposits in the PDB are also increasing day by day. But the sequence stracture gap is not reduced because of the fast sequencing techniques. Homology modelling helps to bridge 

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There are quite a good number of pubhshed papers about homology modelling of proteins [22-25]. For begmners, a brief view of homology modelling is provided. It basically includes the steps shown in Fig. 5.24 [26]. 

Even though every step is cmcial in the generation of a better model, the first steps template recognition and initial alignment are considered as rate limiting. The 

5 Active Site-Directed Pose Prediction Programs for Efficient... 

A great deal of information can be obtained from the primary sequence simply by mapping out the hydrophobic and hydrophilic nature of the amino acids Numeric scales for the hydrophobicity of the amino acids have been developed [17,18], By calculation of a running average of this scale, the identification of transmembrane or membrane-associated regions can be readily identified. This is particularly true for proteins with one region that passes 

For proteins with multiple transmembrane domains, it is not necessary to have exclusively hydrophobic amino acids a pair of amino acids with opposite charges may be present in the lipophilic environment of the membrane. Therefore a search for amphipathic a-helices must be undertaken. Amphipathic helices have well-defined hydrophobic character, the hydrophobic face which would project towards the membrane/lipid environment, and a hydrophilic face, which would project out into the aqueous phase or towards the core of a helix bundle. Often times the distinction is not clear and there are regions of mixed hydrophobic/hydrophilic character. Graphically this can be realized with a helical-wheel representation in which the amino acid side chains project out, at 100 degree intervals, from the view along the long, helical axis. 

The hydrophobic/hydrophilic nature of the different helical faces is clearly illustrated by this projection. The amphipathic character of a segment of a protein can be calculated by use of a Fourier series and calculation of a hydrophobic moment [18], 

The hydrophobic moment gives an orientation of the a-helix with respect to the lipid environment and the aqueous interface of the membrane surface for single a-helices or the hydrophilic core formed from a cluster of transmembrane a-helices (seven and twelve helices are quite common). Other methods, conceptually along similar lines, have produced power spectra which are cleaner, facilitating the identification of the lipophilic moment [12]. 

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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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