Learning generative models for protein fold families
Open accessAbstract
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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Covarying residues in proteins are frequently found to be close together in the tertiary structure.
“Analysis of amino acid residue covariation in deep multiple sequence alignments (MSAs) has revealed that covarying residues in proteins are frequently found to be close together in the tertiary structure.”
From Ultrafast end-to-end protein structure prediction enables high-throughput exploration of uncharacterised proteins (2020) · cites this paper as [2]
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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
- green
- figshare.com
- 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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