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.

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.

Protein

Protein + Ligand

Functional Sites (FS)

Regions that Cluster Around FS

Phylogenetic motifs

• PMs are short sequence fragments that conserve the overall familial phylogeny

• Are they functional?

• How do we detect them?

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

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

Set PSZ Threshold

Regions of PMs

TIM

Phylogenetic Similarity False Positive Expectation

TIM

Phylogenetic Similarity False Positive Expectation

Cytochrome P450

Phylogenetic Similarity False Positive Expectation

Cytochrome P450

Phylogenetic Similarity False Positive Expectation

Enolase

Phylogenetic Similarity False Positive Expectation

Glycerol Kinase

Phylogenetic Similarity False Positive Expectation

Glycerol Kinase

Phylogenetic Similarity False Positive Expectation

Myoglobin

Phylogenetic Similarity False Positive Expectation

Myoglobin

Phylogenetic Similarity False Positive Expectation