EnsembleEGNN: Set-Based Graph Learning for Thermodynamic Ensembles of Cyclic Peptides

Abstract

Molecular graph encoding often relies on a single, static structure, ignoring the thermodynamic ensemble of molecules that are present in solution. Here, we introduce EnsembleEGNN, a foundation model that encodes structural ensembles by processing individual conformers through shared equivariant graph neural network layers, pooled with a set attention block, to make property predictions from the whole ensemble. Pretrained on the CREMP cyclic peptide dataset using multi-task self-supervision, the model is trained to encode the conformational variability of each molecule. When predicting membrane permeability from the CycPeptMPDB benchmark, EnsembleEGNN achieves an $R^2$ of $0.477$ under random cross-validation, outperforming a sequence-only BERT baseline ($R^2=0.439$). This representation advantage persists under rigorous out-of-distribution Butina splits ($R^2=0.401$ versus $0.354$). Finally, a hybrid architecture co-training EnsembleEGNN with the BERT model achieves the highest overall accuracy across both random ($R^2=0.538$) and structural holdout evaluations ($R^2=0.444$). These results demonstrate that encoding conformational ensembles into latent representations improves predictions for properties governed by thermodynamics.

arXiv commentAccepted to Graph Foundation Models workshop at ICML '26. Contains 18 pages, 4 figures, 3 tables, 2 SI items