Learning generative models for protein fold families.
We introduce a new approach to learning statistical models from multiple sequence alignments (MSA) of proteins. Our method, called GREMLIN (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, GREMLIN 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.
Language Technologies Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
Sivaraman
S
Balakrishnan
Hetunandan
H
Kamisetty
Jaime G
JG
Carbonell
Su-In
SI
Lee
Christopher James
CJ
Langmead
D000595:Amino Acid Sequence; D019540:Area Under Curve; D019295:Computational Biology; D003196:Computer Graphics; D003198:Computer Simulation; D008390:Markov Chains; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D054731:PDZ Domains; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein; D013329:Structure-Activity Relationship
D011506:Proteins