MultiPUFFIN: A Multimodal Domain-Constrained Foundation Model for Molecular Property Prediction of Small Molecules

TL;DR

MultiPUFFIN is a multimodal foundation model that predicts multiple thermophysical properties of small molecules with thermodynamic consistency, using domain-informed biases and a multi-source dataset, outperforming larger models with less data.

Contribution

It introduces a novel multimodal, domain-constrained model for molecular property prediction that ensures thermodynamic consistency and handles missing data effectively.

Findings

Achieves mean R^2 of 0.716 on challenging test set.

Outperforms ChemBERTa-2 despite using 2000x less data.

Effectively predicts temperature-dependent properties.

Abstract

Predicting physicochemical properties across chemical space is vital for chemical engineering, drug discovery, and materials science. Current molecular foundation models lack thermodynamic consistency, while domain-informed approaches are limited to single properties and small datasets. We introduce MultiPUFFIN, a domain-constrained multimodal foundation model addressing both limitations simultaneously. MultiPUFFIN features: (i) an encoder fusing SMILES, graphs, and 3D geometries via gated cross-modal attention, alongside experimental condition and descriptor encoders; (ii) prediction heads embedding established correlations (e.g., Wagner, Andrade, van't Hoff, and Shomate equations) as inductive biases to ensure thermodynamic consistency; and (iii) a two-stage multi-task training strategy.Extending prior frameworks, MultiPUFFIN predicts nine thermophysical properties simultaneously. It is trained on a multi-source dataset of 37,968 unique molecules (40,904 rows). With roughly 35 million parameters, MultiPUFFIN achieves a mean $R^2 = 0.716$ on a challenging scaffold-split test set of 8,877 molecules. Compared to ChemBERTa-2 (pre-trained on 77 million molecules), MultiPUFFIN outperforms the fine-tuned baseline across all nine properties despite using 2000x fewer training molecules. Advantages are strikingly apparent for temperature-dependent properties, where ChemBERTa-2 lacks the architectural capacity to incorporate thermodynamic conditions.These results demonstrate that multimodal encoding and domain-informed biases substantially reduce data and compute requirements compared to brute-force pre-training. Furthermore, MultiPUFFIN handles missing modalities and recovers meaningful thermodynamic parameters without explicit supervision. Systematic ablation studies confirm the property-specific benefits of these domain-informed prediction heads.