Homology modeling: Modeller

Homology modeling using the Modeller standalone program and
Modeller through Chimera

1. Homology modeling: Modeller Michael Dolan Source : Aza Toth

2. What is “molecular modeling?” a technique for deriving, representing and manipulating the structures and reactions of  molecules , and those properties that are dependent on these three dimensional structures Drug design Protein homology (or comparative) modeling Nucleic acid 2 º or 3 º structure Protein folding/threading Molecular dynamics Measurements protein-centric

3. Experimental protein structure prediction methods X-ray Diffraction Only a small number of proteins will crystallize A crystal is not the protein’s native environment Very time consuming Nuclear magnetic resonance (NMR) generally explores isolated proteins rather than protein complexes Very time consuming Source : http:// bit.ly /2k4pgZg Source : http:// www.langelab.ch.tum.de /

4. Why the need for computational protein structure prediction? The number of protein structures solved so far are fewer than the number of genes known.

5. Why the need for computational protein structure prediction?

6. Why the need for computational protein structure prediction? The rate of discovery of new proteins far outweighs our ability to functionally characterize them

7. Why the need for computational protein structure prediction? Structures of membrane proteins, ion channels, transporters can be large and difficult to crystallize….

8. Computational methods for protein structure prediction Homology (or “comparative”) modeling Fold Recognition / Threading ab initio today tomorrow

9. Protein Structure D. W. Mount: Bioinformatics , Cold Spring Harbor Laboratory Press, 2001.

10. What is homology modeling? Homology modeling uses homologous sequences with known 3D structures for the prediction of the structure of a target sequence Proteins sharing a significant similarity of sequence can be expected to share also a significant similarity of structure Protein tertiary structure is better conserved than amino acid sequence

11. Source : https:// www.unil.ch / pmf / en /home/ menuinst /technologies/homology- modeling.html

12. Homology modeling workflow Find Template Align sequences Build model Evaluate model Are there any well characterized proteins similar to my protein? What is the position-by-position target/template equivalence? What is the detailed 3D structure of my protein? Measure the model quality. Is my model any good?

13. Limitations of homology modeling Accuracy is highly dependent on the sequence identity between target and templates. Important errors can also happen in regions of the protein that share little sequence identity with the templates, even though the rest of the protein exhibits a high sequence identity. There are still ~5200 protein families with unknown structure outside the range of comparative modeling

14. Sequence Identity 60-100% Comparable to medium resolution NMR Substrate specificity 30-60% Molecular replacement in crystallography Support site-directed mutagenesis through visualization 25- 30% May contain serious errors “twilight zone <25% ? Forget about it…

15. I-TASSER

16. Protein homology modeling using Modeller Dr. Andrej Sali https://salilab.org/modeller/ Free for academic use

17. Homology modeling using Modeller Input: Alignment between target & template Known protein structure of the template Output: Model for the target

18. Homology modeling using Modeller

19. Hands-on Activity: Homology modeling using Modeller Tutorial files: https://shorturl.at /moCS0 Modeling of Lottia pelta malate dehydrogenase Modeller using Chimera web service Modeling of S. aureus tyrosine phosphatase with Modeller using standalone program