Polyformer: a generative framework for thermodynamic modeling of polymeric molecules

TL;DR

Polyformer is a novel generative framework that models the thermodynamic conformational ensembles of polymeric molecules, capturing folding, ensemble distribution, and temperature effects, validated on protein domains.

Contribution

It introduces the first generative model addressing folding, conformational ensembles, and temperature dependence simultaneously for polymeric molecules.

Findings

Good agreement with Molecular Dynamics trajectories for protein domains.

Successfully models conformational ensembles at different temperatures.

Abstract

The classic paradigm of structural biology is that the sequence of a biomolecule (protein, nucleic acid, lipid, etc) determines its conformation (shape) which determines its biological function. Protein folding programs like AlphaFold address this paradigm by predicting the single best conformation given a sequence that defines the molecule. However, biomolecules are not static structures, and their conformational ensemble determines their function. We present the Polyformer -- a generative framework for thermodynamic modeling of polymeric molecules. Given the sequence and temperature (or another thermodynamic variable), the Polyformer generates conformations faithful to the molecule's thermodynamic conformational ensemble. It is the first generative model that solves three problems simultaneously: how does a molecule fold, what is its conformational ensemble, and how does the conformational ensemble change as we change physical temperature. As a concrete test case, we apply Polyformer to protein domains with 50-111 residues and report good agreement of model predictions to Molecular Dynamics (MD) trajectories.