Protein fold recognition and ab_initio modeling

Protein fold recognition and ab_initio modeling

1. Fold recognition and ab initio protein modeling Michael Dolan 6/26/18 Source : Aza Toth

2. What if there is no homolog?

3. Computational methods for protein structure prediction Homology (or “comparative”) modeling used for proteins which have their homologous protein structures deposited in the  Protein Data Bank  (PDB) used to model those proteins which have the same fold as proteins of known structures, but do not have homologous proteins with known structure Fold recognition / threading ab initio modeling Uses the laws of physics along with protein fragments to construct a model using the laws of physics (energy function)

4. Protein fold recognition Can be applied when homology modeling methods provide no reliable prediction attempt to identify a model fold for a given target sequence among the known folds even if no sequence similarity can be detected

5. Protein Fold Recognition Basic premise Similar sequence implies similar structure but not all similar structures have similar sequence structure is evolutionary more conserved than sequence number of unique structural folds in nature is fairly small

6. Structures conserve more than just sequence….

7. SCOP: Structural Classification of Proteins

8. Similar structures can be found among proteins with no sequence similarity Chap. 11 Protein Structures: Published by Eleanore Bruce

9. 3.6 Å 5% ID NK- lysin (1nkl) Bacteriocin (1e68) Less protein folds compare to sequence diversity

10. Protein Fold Recognition / Threading Which of the known folds is likely to be similar to the (unknown) fold of a new protein when only its amino-acid sequence is known?

11. Predicting Secondary Structure From Primary Structure TEAVD AATAEKVFKQY ANDNGVDG EWTYDDATKTF TVTEK TEAVD AWTVEKAFKTF ANDNGVDG AWTVEKAFKTF TVTEK Replace both sequences with an engineered peptide Source: Minor and Kim. 1996. Nature 380:730-734 a -helix b -strand

12. Protein Threading Threading method defines the "fitness" of the query from the structural environment of the template structure. Sequences are fitted directly onto the backbone coordinates of known protein structures Matching of sequences to backbone coordinates is performed in 3D space, incorporating specific pair interactions explicitly

13. Ab initio / de novo methods Build protein 3D structures from sequence alone based on physical principles https:// doi.org /10.1371/journal.pone.0032637

14. Protein intramolecular interactions https:// www.fastbleep.com /biology-notes/40/1175

15. Let’s pause and think about this problem… For a protein of 200 residues and considering only 3 backbone angles ( F,Y, and W )… …there are 3 200 possibilities. There are estimated to be 10 82 atoms in universe.

16. Rosetta

17. Fragment-based, ab initio modeling Sections of a sequence are subjected to secondary structure prediction Assembled in 3D space, looking for lowest energy configurations

18. Fragment-based folding using Rosetta

19. ab initio modeling Challenges: scoring function fast method for sampling conformations Advantages: Can work for novel folds helps to understand the folding process Disadvantages: applicable to short sequences only; monomers time consuming misleading results?

20. Hands on Exercises Robetta : A web server for ab initio modeling Rosetta: Command line suite of programs for ab initio modeling (see assoc tutorial)

21. Robetta : full-chain protein structure prediction server http://robetta.bakerlab.org

22. Rosetta analysis