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

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 R2 of 0.477 under random cross-validation, outperforming a sequence-only BERT baseline (R2=0.439). This representation advantage persists under rigorous out-of-distribution Butina splits (R2=0.401 versus 0.354). Finally, a hybrid architecture co-training EnsembleEGNN with the BERT model achieves the highest overall accuracy across both random (R2=0.538) and structural holdout evaluations (R2=0.444). These results demonstrate that encoding conformational ensembles into latent representations improves predictions for properties governed by thermodynamics.