Cited by 316Protein Structure and DynamicsGenomics and Phylogenetic StudiesMachine Learning in Bioinformatics

Learning generative models for protein fold families

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Balakrishnan, Sivaraman, Kamisetty, Hetunandan, Carbonell, Jaime G., Lee, Su‐In, Langmead, Christopher James·2011·Proteins: Structure, Function, and Bioinformatics

Abstract

We introduce a new approach to learning statistical models from multiple sequence alignments (MSA) of proteins. Our method, called G REMLIN(Generative REgularized ModeLs of proteINs), learns an undirected probabilistic graphical model of the amino acid composition within the MSA. The resulting model encodes both the position‐specific conservation statistics and the correlated mutation statistics between sequential and long‐range pairs of residues. Existing techniques for learning graphical models from MSA either make strong, and often inappropriate assumptions about the conditional independencies within the MSA (e.g., Hidden Markov Models), or else use suboptimal algorithms to learn the parameters of the model. In contrast, G REMLIN makes no a priori assumptions about the conditional independencies within the MSA. We formulate and solve a convex optimization problem, thus guaranteeing that we find a globally optimal model at convergence. The resulting model is also generative, allowing for the design of new protein sequences that have the same statistical properties as those in the MSA. We perform a detailed analysis of covariation statistics on the extensively studied WW and PDZ domains and show that our method out‐performs an existing algorithm for learning undirected probabilistic graphical models from MSA. We then apply our approach to 71 additional families from the PFAM database and demonstrate that the resulting models significantly out‐perform Hidden Markov Models in terms of predictive accuracy. Proteins 2011; © 2011 Wiley‐Liss, Inc.

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  1. [7][7] David Maxwell Chickering and Craig Boutilier. Optimal structure identification with greedy search. Journal of Machine Learning Research , 3:507-554, 2002. -
  2. [23][23] Peter Spirtes, Clark Glymour, and Richard Scheines. Causation, Prediction, and Search (Lecture Notes in Statistics) . Springer-Verlag, 1993. -

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Authors
Balakrishnan, S., Kamisetty, H., Carbonell, J. G., Lee, S., & Langmead, C. J.
Affiliations
  • Carnegie Mellon University (US)
  • University of Washington (US)
Corresponding author
  • Balakrishnan, Sivaraman
  • Kamisetty, Hetunandan
  • Langmead, Christopher James
Venue
Proteins: Structure, Function, and Bioinformatics
Publisher
Wiley
Published
2011-01-25
Volume
79
Issue
4
Pages
1061-1078
ISSN
  • 0887-3585 (ISSN-L)
  • 1097-0134
OpenAlex
W2169478909
Cited by
316
References
52
Citations by year
2026: 4 · 2025: 9 · 2024: 23 · 2023: 23 · 2022: 21 · 2021: 43 · 2020: 27 · 2019: 43 · 2018: 24 · 2017: 26 · 2016: 21 · 2015: 22 · 2014: 10 · 2013: 9 · 2012: 8
FWCI
2.60
Type
journal article
Language
en
Open access
Locations
  • Proteins Structure Function and Bioinformatics (publishedVersion)
  • PubMed (publishedVersion)
  • KiltHub Repository (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • KiltHub Repository
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
Keywords
Gremlin, multiple sequence alignment, amino acid composition, correlated mutations, protein sequence design, convex optimization, WW domain, PDZ domain, Pfam, protein structure prediction
MeSH terms
Amino Acid Sequence, Computer Graphics, Computer Simulation, Markov Chains, Models, Chemical, Models, Molecular, Proteins, Structure-Activity Relationship, Models, Statistical, Sequence Alignment, Protein Folding, Computational Biology, Area Under Curve, Sequence Analysis, Protein, PDZ Domains

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