Leonardo Trevisan Mota
Evolutionary Dynamics and Context-Dependent Accessibility in DCA and Transformer-Based Protein Sequence Models.
Rel. Andrea Pagnani, Martin Weigt. Politecnico di Torino, Master of science program in Physics Of Complex Systems, 2026
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Abstract
Protein evolution can be studied through models that learn statistical constraints from natural sequence families. These models are often evaluated either as mutation predictors or as generators of natural-like sequences. In this thesis I ask a different question: when a learned protein model is turned into an evolutionary landscape, what kind of long-time sequence exploration does it produce? I compare four models of protein families: Boltzmann-machine Direct Coupling Analysis, asymmetric pseudolikelihood DCA, an autoregressive Transformer, and a masked Transformer. A central part of the work is the development and implementation of evolutionary dynamics for the Transformer-based models, extending the approach that had previously been used for DCA-based landscapes.
This comparison separates two classes of models: bmDCA and the autoregressive Transformer define a joint probability distribution over full sequences, while plmDCA and the masked Transformer are based on local conditional probabilities
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