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Homology Modeling

Homology Modeling. Limitations of Experimental Methods. Annotated proteins in the databank: ~ 100,000. Total number including ORFs: ~ 700,000. Proteins with known structure: ~5,000 !. Protein modeling. Provide a solid basis for, structure-based drug design

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Homology Modeling

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  1. Homology Modeling

  2. Limitations of Experimental Methods Annotated proteins in the databank: ~ 100,000 Total number including ORFs: ~ 700,000 Proteins with known structure: ~5,000 !

  3. Protein modeling • Provide a solid basis for, • structure-based drug design • analysis of protein function, interactions, antigenic behavior • rational design of proteins with increased stability or novel functions

  4. Homology Modeling • Based on two major observations: • The structure of a protein is • determined by its amino acid sequence • 2) Structure is much more conserved than sequence • during evolution

  5. What’s homology modeling? Predicts the three-dimensional structure of a given protein sequence (target) based on an alignment to one or more known protein structures (templates). If similarity between the target sequence and the template sequence is detected, structural similarity can be assumed. In general, 30% sequence identity is required to generate an useful model.

  6. Accuracy and application of protein structure

  7. Does sequence similarity implies structure similarity? Safe Zone Twilight Zone

  8. Structure prediction by homology modeling

  9. In summary: homology modeling steps 1) Template recognition & initial alignment 2) Alignment correction 3) Backbone generation 4) Loop modeling 5) Side-chain modeling 6) Model optimization 7) Model validation

  10. Steps in Homology Modeling Step 1: Template Recognition and Initial Alignment:- In practice, one just feeds the query sequence to one of the countless BLAST servers on the web, selects a search of the PDB, and obtains a list of hits—the modeling templates and corresponding alignments

  11. BLAST Basic Local Alignment Search Tool • Most widely used bioinformatics program • Emphasizes speed over sensitivity (speed is vital to making the algorithm practical on the huge genome databases)

  12. Overview - METABOLISM

  13. Sites of biotransformation • where ever appropriate enzymes occur; plasma, kidney, lung, gut wall and LIVER • the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation

  14. 2. An alignment matrix By comparing thousands of sequences and sequence families, it became clear that the opening of gaps is about as unlikely as at least a couple of nonidentical residues in a row. Opening penalty: for every new gap Gap extension penalty: for every residue that is skipped in the alignment

  15. Step 2: Alignment Correction Sometimes it may be difficult to align two sequences in a region where the percentage sequence identity is very low. One can then use other sequences from homologous proteins to find a solution. LTLTLTLT −LTLTLTLT− TYTYTYTYT TYTYTYTYT YAYAYAYAVY −YAYAYAYAY

  16. 2 is correct, because it leads to a small gap, compared to a huge hole associated with alignment 1.

  17. 7 Sequence 1 Template 9 7.5 Å 1.3 Å 5 11

  18. Step 3: Backbone Generation:- One simply copies the coordinates of those template residues that show up in the alignment with the model sequence. If two aligned residues differ, only the backbone coordinates (N,Cα,C and O) can be copied. If they are the same, one can also include the side chain.

  19. Step 4: Loop Modeling:- There are two main approaches to loop modeling:- 1). Knowledge based: one searches the PDB for known loops with endpoints that match the residues between which the loop has to be inserted and simply copies the loop conformation. 2). Energy based: as in true ab initio fold prediction, an energy function is used to judge the quality of a loop

  20. Step 5: Side-Chain Modeling:- Comparing the side-chain conformations (rotamers) of residues that are conserved in structurally similar proteins Similar torsion angle about the Cα −Cβ bond - It is therefore possible to simply copy conserved residues entirely from the template to the model

  21. Step 6: Model Optimization:- Energy = Stretching Energy +Bending Energy +Torsion Energy +Non-Bonded Interaction Energy

  22. Step 7: Model Validation Model should be evaluated for: - correctness of the overall fold/structure - errors over localized regions - stereochemical parameters: bond lengths, angles, etc

  23. Step 7: Model Validation

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