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Protein Classification. A comparison of function inference techniques . Why do we need automated classification?. Sequencing a genome is only the first step. Between 35-50% of the proteins in sequenced genomes have no assigned functionality.

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protein classification

Protein Classification

A comparison of function inference techniques

why do we need automated classification
Why do we need automated classification?
  • Sequencing a genome is only the first step.
  • Between 35-50% of the proteins in sequenced genomes have no assigned functionality.
  • Direct observation of function is costly, time consuming, and difficult.
protein domains
Protein Domains
  • The tertiary structure of many proteins is built from several domains.
  • Often each domain has a separate function to perform for the protein, such as:
  • binding a small ligand (e.g., a peptide in the molecule shown here)
  • spanning the plasma membrane (transmembrane proteins)
  • containing the catalytic site (enzymes)
  • DNA-binding (in transcription factors)
  • providing a surface to bind specifically to another protein
  • In some (but not all) cases, each domain in a protein is encoded by a separate exon in the gene encoding that protein.
inference through sequence similarity

Inference through sequence similarity

ProtoMap: Automatic Classification of Protein Sequences, a Hierarchy of Protein Families, and Local Maps of the Protein Space (1999)

observations
Observations
  • Sometimes you don’t know where the domains are.
  • It is generally accepted that two sequences with over 30% identity are likely to have the same fold.
  • Homologous proteins have similar functions.
  • Homology is a transitive relationship.
departures
Departures
  • Authors do not attempt to define protein domains or motifs.
  • Not dependant on predefined groups or classifications.
  • Chart the space of all proteins in SWISSPROT, as opposed to individual families
  • Produce global organization of sequences.
algorithm overview
Algorithm Overview
  • We construct a weighted graph where the nodes are protein sequences and the edges are similarity scores.
  • Cluster the network considering only those edges above some threshold.
  • Decrease similarity threshold and repeat.
measuring sequence similarity
Measuring Sequence Similarity
  • Expectation value used. This the normalized probability of the similarity occurring at random.
  • Lower value implies logarithmically stronger similarity.
finding homologies
Finding Homologies
  • Very difficult to distinguish a clear threshold between homology and chance similarity.
  • Authors chose e = .1, .1, and .001 for SW, FASTA, and BLAST, respectively.
  • Spent a lot of time empirically determining these thresholds.
clustering
Clustering

Clustering is done iteratively.

Start with a threshold of E < 10-100

Cluster and increase threshold by a factor of 105

Sublinear threshold prevents the collapse of sequence space

protomap results
ProtoMap: Results
  • Produces well-defined groups which correlate strongly to protein families in PROSITE and Pfam.
protomap limitations
ProtoMap: Limitations
  • Analysis performs poorly by families dominated by short/local domains (PH, EGF, ER_TARGET, C2, SH2, SH3, ect…)
  • High scoring, low complexity segments can lead to nonhomogeneous clusters.
  • “Hard” clustering vs. “Soft” clustering
  • Has difficulty classifying multidomain proteins.
protomap future directions
ProtoMap: Future Directions
  • 3D structure/fold
  • Biological function
  • Domain content
  • Cellular location
  • Tissue specificity
  • Source organism
  • Metabolic pathways
inference through protein interaction networks

Inference through protein interaction networks

Functional Classification of Proteins for the Prediction of Cellular Function from a Protein-Protein Interaction Network (2003)

prodistin
PRODISTIN
  • Very similar to ProtoMap, only the data used to produce the graph is a list of binary protein-protein interactions instead of sequence similarity scores
  • Sequence similarity not a dominating factor in PRODISTIN clusters
problems with prodistin
Problems with PRODISTIN
  • Paucity of protein-protein interaction data (average # of connections = 2.6)
  • Either very robust or very indiscriminant
problems multidomain and nonlocal proteins
Problems: Multidomain and Nonlocal Proteins
  • protein kinases
  • hydrolases
  • ubiquitin…

PRODISTIN: Present problems in clustering by biochemical function

ProtoMap: Can create undesired connection among unrelated groups

scale free networks
Scale-Free Networks
  • Node connection probability follows a power law distribution
  • Maximum degree of separation grows as O(lg n)
  • Highly robust under noise, except at hubs and superhubs.

P(linking to node i)

metabolic networks
Metabolic Networks
  • The E. coli metabolic network is scale-free.
  • Actually, the metabolic networks of all organisms in all three domains of life appear to be scale-free (43 examined)
  • The network diameter of all 43 metabolic networks is the same, irrespective of the number of proteins involved.
  • Is this counter-intuitive? Yes.

http://biocomplexity.indiana.edu/research/bionet/

protein domain networks
Protein Domain Networks
  • Protein Domains – Nature’s take on writing modular code
  • Reconciles apparent paradox of a fixed network diameter across species – despite vast differences in complexity (some human proteins have 130 domains)
  • Occurrence of specific protein domains in multidomain proteins is scale-free.

http://mbe.oupjournals.org/cgi/content/full/18/9/1694

protein domain graphs
Protein Domain Graphs
  • Prosite domains have a distribution following the power-law function f(x) = a(b + x)-c, with c = .89. There are few highly connected domains and many rarely connected ones.
  • ProDom and Pfam domains follow the power function

y = 2.5 for ProDom

y = 1.7 for Pfam

conclusions
Conclusions
  • The accuracy of both ProtoMap and PRODISTIN is limited because they make the tacit assumption of a random network topology.
  • Protein-Protein interaction networks have scale-free topology, foiling PRODISTIN
  • Protein Domain networks have scale-free topology, foiling ProtoMap
  • Any protein classification algorithm that performs better than ProtoMap is probably going to have to address this issue.