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Homology Modeling David Shiuan Department of Life Science and Institute of Biotechnology National Dong Hwa University

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Homology Modeling. David Shiuan Department of Life Science and Institute of Biotechnology National Dong Hwa University. Why Modeling ?. X-ray diffraction  electron diffraction map  electron density map  Missing chains and residues in PDB structures No structure available. - PowerPoint PPT Presentation

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Page 1: Homology Modeling

Homology Modeling

David Shiuan

Department of Life Scienceand Institute of Biotechnology

National Dong Hwa University

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Why Modeling ?

X-ray diffraction electron diffraction map electron density map

Missing chains and residues in PDB structures

No structure available

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Erwin Schrodinger

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John Pople1964 NobleComputation Chemistry

Walter Kohn1960 NobleDensity-Function theory

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Polypeptide Chain

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Structural Models are a unique source of information

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Modeling – Prediction of 3D Structures

Homology Modeling Structures of similar molecules available

Threading Prediction-based threading detecting the fold type an

d aligning a protein of unknown structure and a protein of known structure for low levels of sequence identity ( < 25%)

Ab initio predicts the structure of proteins from the sequence a

nd using molecular energy calculations (Schrodinger equation), do not use experimental parameters.

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Threading, A new approach to protein fold recognition. Nature 358

(1992 ) 86-89 An alternative strategy of recognizing known moti

fs or folds in sequences looks promising

Threading is an approach to fold recognition which used a detailed 3-D representation of protein structure. The idea was to physically "thread" a sequence of amino acid side chains onto a backbone structure (a fold) and to evaluate this proposed 3-D structure using a set of pair potentials and (importantly) a separate solvation potential.

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View saccharide with JMol-Applet Chemis3D-Applet

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Bystroff C & Shao Y. (2002). Fully automated ab initio protein structure prediction using I-SITES, HMMSTR and ROSETTA. Bioinformatics 18 Suppl 1, S54-61.

Ab initioStructure Prediction

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Comparative Protein Modelling Proteins with high sequence similarity is reflected b

y distinct structure similarity

Comparative protein modelling (Homology Modeling) is presently the most reliable method.

Comparative model building consist of the extrapolation of the structure for a new (target) sequence from the known 3D-structure of related family members (templates).

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Building The Model 1. Framework construction

By averaging the position of each atom in the target sequence, based on the location of the corresponding atoms in the template

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Building The Model 2. Building non-conserved

loops Although most of the known

3D-structures available share no overall similarity with the template, there may be similarities in the loop regions, and these can be inserted as loop structure in the new protein model

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Building The Model 3. Completing the backbone

Since the loop building only adds C atoms, the backbone carbonyl and nitrogens must be completed in these regions.

This step can be performed by using a library of pentapeptide backbone fragments derived from the PDB entries

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Building The Model4. Adding side chains

For many of the protein side chains there is no structural information available in the templates. These cannot therefore be built during the framework generation and must be added later

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Building The Model5. Model refinement

Idealisation of bond geometry and removal of unfavourable non-bonded contacts can be performed by energy minimisation with force fields such as CHARMM, AMBER or GROMOS.

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How to Superimpose Two Proteins

Open the PDB file 11MUP Open the PDB file 21OBP Color by secondary structure Use the "Iterative Magic Fit"

or the“Improve Fit" item of the "Tools" menu

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How SWISS-MODEL works

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Probabilities of SWISS-MODEL accuracy for target-template identity classes

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224 aa

224 aa

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We have identified three new families of insulin homologs in C. elegans.

Comparative protein modelling remarkably confirms these predictions

Example/Swiss Model:Insulin-like growth factors in C. elegans.