Protein Functional Site Prediction

1. Protein Functional Site Prediction • The identification of protein regions responsible for stability and function is an especially important post-genomic problem • With the explosion of genomic data from recent sequencing efforts, protein functional site prediction from only sequence is an increasingly important bioinformatic endeavor.

2. What is a “Functional Site”? • Defining what constitutes a “functional site” is not trivial • Residues that include and cluster around known functionality are clear candidates for functional sites • We define a functional site as catalytic residues, binding sites, and regions that clustering around them.

3. Protein

4. Protein + Ligand

5. Functional Sites (FS)

6. Regions that Cluster Around FS

7. Phylogenetic motifs • PMs are short sequence fragments that conserve the overall familial phylogeny • Are they functional? • How do we detect them?

8. Phylogenetic motifs • PMs are short sequence fragments that conserve the overall familial phylogeny • Are they functional? • How do we detect them? • First we design a simple heuristic to find them • Then we see if the detected sites are functional

9. Phylogenetic Motif Identification • Compare all windowed trees with whole tree and keep track of the partition metric scores • Normalize all partition metric scores by calculating z-scores • Call these normalized scores Phylogenetic Similarity Z-scores (PSZ) • Set a PSZ threshold for identifying windows that represent phylogenetic motifs

10. Set PSZ Threshold

11. Regions of PMs

12. TIM Phylogenetic Similarity False Positive Expectation

13. TIM Phylogenetic Similarity False Positive Expectation

14. Cytochrome P450 Phylogenetic Similarity False Positive Expectation

15. Cytochrome P450 Phylogenetic Similarity False Positive Expectation

16. Enolase Phylogenetic Similarity False Positive Expectation

17. Glycerol Kinase Phylogenetic Similarity False Positive Expectation

18. Glycerol Kinase Phylogenetic Similarity False Positive Expectation

19. Myoglobin Phylogenetic Similarity False Positive Expectation

20. Myoglobin Phylogenetic Similarity False Positive Expectation