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Characterization of Secondary Structure of Proteins using Different Vocabularies. Madhavi K. Ganapathiraju Language Technologies Institute Advisors Raj Reddy, Judith Klein-Seetharaman, Roni Rosenfeld. 2 nd Biological Language Modeling Workshop Carnegie Mellon University May 13-14 2003.
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Characterization of Secondary Structure of Proteins using Different Vocabularies Madhavi K. Ganapathiraju Language Technologies Institute Advisors Raj Reddy, Judith Klein-Seetharaman, Roni Rosenfeld 2nd Biological Language Modeling Workshop Carnegie Mellon University May 13-14 2003
Presentation overview • Classification of Protein Segments by their Secondary Structure types • Document Processing Techniques • Choice of Vocabulary in Protein Sequences • Application of Latent Semantic Analysis • Results • Discussion
Secondary Structure of Protein Sample Protein: MEPAPSAGAELQPPLFANASDAYPSACPSAGANASGPPGARSASSLALAIAITAL YSAVCAVGLLGNVLVMFGIVRYTKMKTATNIYIFNLALADALATSTLPFQSA… Sample Protein: MEPAPSAGAELQPPLFANASDAYPSACPSAGANASGPPGARSASSLALAIAITAL YSAVCAVGLLGNVLVMFGIVRYTKMKTATNIYIFNLALADALATSTLPFQSA…
Application of Text Processing Letters Words Sentences Letter counts in languages Word counts in Documents Residues Secondary Structure ProteinsGenomes Can unigrams distinguish Secondary Structure Elements from one another
Unigrams for Document Classification • Word-Document matrix • represents documents in terms of their word unigrams “Bag-of-words” model since the position of words in the document is not taken into account
Document Vectors Doc-1
Document Vectors Doc-2
Document Vectors Doc-3
Document Vectors Doc-N
Document Comparison • Documents can be compared to one another in terms of dot-product of document vectors = .*
Document Comparison • Documents can be compared to one another in terms of dot-product of document vectors = .*
Document Comparison • Documents can be compared to one another in terms of dot-product of document vectors = .* • Formal Modeling of documents is • presented in next few slides…
Vector Space Model construction • Document vectors in word-document matrix are normalized • By word counts in entire document collection • By document lengths • This gives a Vector Space Model (VSM) of the set of documents • Equations for Normalization…
Word count normalization (Word count in document) (document length) (depends on word count in corpus) t_i is the total number of times word i occurs in the corpus
Word-Document Matrix Normalized Word-Document Matrix
Use of Vector Space Model • A query document is also represented as a vector • It is normalized by corpus word counts • Documents related to the query-doc are identified • by measuring similarity of document vectors to the query document vector
Protein Secondary Structure • Dictionary of Secondary Structure Prediction: annotation of each residue with its structure • based on hydrogen bonding patterns and geometrical constraints • 7 DSSP labels for PSS: • H • G • B • E • S • I • T Helix types Strand types Coil types
Example PKPPVKFNRRIFLLNTQNVINGYVKWAINDVSLALPPTPYLGAMKYNLLH Residues PKPPVKFNRRIFLLNTQNVINGYVKWAINDVSLALPPTPYLGAMKYNLLH ____SS_SEEEEEEEEEEEETTEEEEEETTEEE___SS_HHHHHHTT_TT ____SS_SEEEEEEEEEEEETTEEEEEETTEEE___SS_HHHHHHTT_TT DSSP Key to DSSP labels T, S, I,_: Coil E, B: Strand H, G: Helix
Reference Model • Proteins are segmented into structural Segments • Normalized word-document matrix • constructed from structural segments
Example Residues PKPPVKFNRRIFLLNTQNVINGYVKWAINDVSLALPPTPYLGAMKYNLLH PKPPVKFNRRIFLLNTQNVINGYVKWAINDVSLALPPTPYLGAMKYNLLH ____SS_SEEEEEEEEEEEETTEEEEEETTEEE___SS_HHHHHHTT_TT ____SS_SEEEEEEEEEEEETTEEEEEETTEEE___SS_HHHHHHTT_TT DSSP Structural Segments obtained from the given sequence: PKPPVKFN RRIFLLNTQNVI NG YVKWAI ND VSL ALPPTP YLGAMKY NLLH
Example Residues PKPPVKFNRRIFLLNTQNVINGYVKWAINDVSLALPPTPYLGAMKYNLLH PKPPVKFNRRIFLLNTQNVINGYVKWAINDVSLALPPTPYLGAMKYNLLH ____SS_SEEEEEEEEEEEETTEEEEEETTEEE___SS_HHHHHHTT_TT ____SS_SEEEEEEEEEEEETTEEEEEETTEEE___SS_HHHHHHTT_TT DSSP Structural Segments obtained from the given sequence: PKPPVKFN RRIFLLNTQNVI NG YVKWAI ND VSL ALPPTP YLGAMKY NLLH Unigrams in the structural segments
Structural Segments Amino-acid Structural-Segment Matrix Amino Acids
Structural Segments Amino-acid Structural-Segment Matrix Amino Acids Similar to Word-Document Matrix
… Document Vectors WordVectors
Document Vectors Query Vector WordVectors …
Data Set used for PSSP • JPred data • 513 protein sequences in all • <25% homology between sequences • Residues & corresponding DSSP annotations are given • We used • 50 sequences for model construction (training) • 30 sequences for testing
Classification • Proteins from test set • segmented into structural elements • Called “query segments” • Segment vectors are constructed • For each query segment • ‘n’ most similar reference segment vectors are retrieved • Query segment is assigned same structure as that of the majority of the retrieved segments* *k-nearest neighbour classification
Compare Similarities 3 most similar reference vectors Coil Majority voting out of 3-most similar reference vectors = = Structure type assignment to QVector Reference Model Query Vector Key HelixStrandCoil Hence Structure-type assigned to Query Vector isCoil
Choice of Vocabulary in Protein Sequences • Amino Acids • But Amino acids are • Not all distinct.. • Similarity is primarily due to chemical composition So, • Represent protein segments in terms of “types” of amino acids • Represent in terms of “chemical composition”
Representation in terms of “types” of AA • Classify based on Electronic Properties • e- donors: D,E,A,P • weak e-donors: I,L,V • Ambivalent: G,H,S,W • weak e- acceptor: T,M,F,Q,Y • e- acceptor: K,R,N • C(by itself, another group) • Use Chemical Groups
Results of Classification with “AA” as words Leave 1-out testing of reference vectors Unseen query segments
Results with “chemical groups” as words • Build VSM using both reference segments and test segments • Structure labels of reference segments are known • Structure labels of query segments are unknown
Modification to Word-Document matrix • Latent Semantic Analysis • Word document matrix is transformed • by “Singular Value Decomposition”
LSA results for Different Vocabularies Amino acids LSA Types of Amino acid LSA Chemical Groups LSA
Model construction using all data Matrix models constructed using both reference and query documents together. This gives better models both for normalization and in construction Of latent semantic model Amino Acid Chemical Groups Amino acid types
Applications • Complement other methods for protein structure prediction • Segmentation approaches • Protein classifications as all-alpha, all-beta, alpha+beta or alpha/beta types • Automatically assigning new proteins into SCOP families
References • Kabsch, Sander “Dictionary of Secondary Structure Prediction”, Biopolymers. • Dwyer, D.S., Electronic properties of the amino acid side chains contribute to the structural preferences in protein folding. J Biomol Struct Dyn, 2001. 18(6): p. 881-92. • Bellegarda, J., “Exploiting Latent Semantic Information in Statistical Language Modeling”, Proceedings of the IEEE, Vol 88:8, 2000.
Use of SVD • Representation of Training and test segments very similar to that in VSM • Structure type assignment goes through same process, except that it is done with the LSA matrices
Classification of Query Document • Query Document is assigned the same Structure as of those retrieved by similarity measure • Majority voting* • A query document is also represented as a vector • It is normalized by corpus word counts • Documents related to the query are identified • by measuring similarity of document vectors to the query document vector *k-nearest neighbour classification
Notes… • Results described are per-segment • Normalized Word document matrix does not preserve document lengths • Hence “per residue” accuracies of structure assignments cannot be computed