Protein Folding Programs

1. Protein Folding Programs By Asım OKUR CSE 549 November 14, 2002

2. Protein Structure • DNA Sequence  Protein Sequence  Structure  (Mis)function • It is believed that all the information necessary to determine the structure of a protein is present in its primary sequence.

3. Protein Folding Programs • Protein folding is one of the biggest computational challenges • Different types of folding and structure predictions programs • Simulations • Homology Modeling Approaches

4. Simulations • Simulate the real behavior of proteins • High detail, short time scales • 2 main simulation types • Molecular Dynamics • Monte Carlo

5. The Energy Function • Calculate energies for each particle • Since long range interactions important for each pair of particles the pair-wise interactions should be calculated

6. Homology Modeling • Template Selection and Fold Assignment • Target – Template Alignment • Model Building • Loop Modeling • Sidechain Modeling • Model Evaluation

7. Fold Assignment and Template Selection • Identify all protein structures with sequences related to the target, then select templates • 3 main classes of comparison methods • Compare the target sequence with each database sequence independently, pair-wise sequence – sequence comparison, BLAST and FASTA • Multiple sequence comparisons to improve sensitivity, PSI-BLAST • Threading or 3-D template matching methods

8. Target – Template Alignment • Most important step in Homology Modeling • A specialized method should be used for alignment • Over 40% identity the alignment is likely to be correct. • Regions of low local sequence similarity become common when overall sequence identity is under 40%. (Saqi et al., Protein Eng. 1999) • The alignment becomes difficult below 30% sequence identity. (Rost, Protein Eng. 1999)

9. Model Building • Construct a 3-D model of the target sequence based on its alignment on template structures • Three different model building approaches • Modeling by rigid body assembly • Modeling by segment matching • Modeling by satisfaction of spatial restraints • Accuracies of these models are similar • Template selection and alignment have larger impact on the model

10. Screenshots from the Homology Modeling Server Swiss-Model • Construct a framework using known protein structures • Generate the location of the target amino acids on the framework • If loop regions not determined, additional database search or short simulations Swiss-MOD Web Server

11. Procedure of the MODELLER program • After obtaining restraints run a geometry optimization or real-space optimization to satisfy them

12. Errors in Homology Models • Errors in sidechain packing • Distortions and shifts in correctly aligned regions • Errors in regions without a template

13. d. Errors due to misalignment e. Incorrect templates

14. Model Building Programs

16. Applications

17. Critical Assessment of protein Structure Prediction (CASP) Venclovas et al. Proteins, 2001

18. Critical Assessment of protein Structure Prediction (CASP) Venclovas et al. Proteins, 2001

19. Conclusions • Computer Simulations are powerful to show detailed motions but they cannot cover long enough time spans to simulate folding for large systems • Homology Modeling techniques can be successful if the target protein has a known fold • The higher the sequence similarity the more likely the model will be successful • With the implementation of better techniques the errors in fold assignment, alignment, and sidechain and loop modeling are decreasing • Theoretically, if at least one member of every possible fold is known, it is possible to predict the structure of every coding sequence to within a certain accuracy