# Geometry-Informed Parameter-Efficient Fine-Tuning of Pre-trained Molecular GNNs for Blood-Brain Barrier Permeability Prediction

arXiv: https://arxiv.org/abs/2608.04257 · HTML: https://mlsanity.com/paper/2608.04257/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 9 of its 38 references that are in the map.
- First posted on arXiv 4 Aug 2026.

## Builds on (most cited first, 9 of 9)

- [XGBoost: A Scalable Tree Boosting System](https://mlsanity.com/paper/1603.02754/) (2016)
- [Parameter-Efficient Transfer Learning for NLP](https://mlsanity.com/paper/1902.00751/) (2019)
- [Graph Contrastive Learning with Augmentations](https://mlsanity.com/paper/2010.13902/) (2020)
- [Strategies for Pre-training Graph Neural Networks](https://mlsanity.com/paper/1905.12265/) (2019)
- [Analyzing Learned Molecular Representations for Property Prediction](https://mlsanity.com/paper/1904.01561/) (2019)
- [SimGRACE: A Simple Framework for Graph Contrastive Learning without Data Augmentation](https://mlsanity.com/paper/2202.03104/) (2022)
- [One Prompt Fits All: Universal Graph Adaptation for Pretrained Models](https://mlsanity.com/paper/2509.22416/) (2025)
- [Molecule Graph Networks with Many-body Equivariant Interactions](https://mlsanity.com/paper/2406.13265/) (2024)
- [HLSAD: Hodge Laplacian-based Simplicial Anomaly Detection](https://mlsanity.com/paper/2505.24534/) (2025)

## Abstract (arXiv)

Blood-brain barrier permeability (BBBP) prediction is a critical screening task in central nervous system drug discovery, where candidate molecules must be assessed for whether they can cross, or should be prevented from crossing, the blood-brain barrier. However, this task remains challenging because of limited, class-imbalanced datasets and sensitivity to molecular structure. Recent advances in deep learning have established graph neural networks (GNNs) as a powerful approach for molecular representation learning, while pre-trained molecular GNNs provide transferable knowledge for downstream tasks. However, full fine-tuning is often parameter-inefficient and prone to overfitting, whereas existing parameter-efficient fine-tuning (PEFT) methods mainly adapt node features or the two-dimensional covalent graph, limiting their ability to capture three-dimensional geometry and second-order interactions. To address these limitations, we propose BBBP-GeoPEFT, a geometry-informed PEFT framework for pre-trained molecular GNNs. BBBP-GeoPEFT constructs distance-based graphs at multiple cutoffs and their corresponding line graphs from molecular conformers to capture spatial atom and second-order edge interactions. Lightweight auxiliary geometric graph encoders generate cutoff-specific representations, which are incorporated into each pre-trained layer through node-wise cutoff attention and gated residual connections. This design preserves pre-trained knowledge while incorporating permeability-relevant geometric information with a small trainable-parameter budget. Experiments on a curated BBBP dataset show that BBBP-GeoPEFT achieves competitive performance compared with full fine-tuning and representative PEFT baselines. Under both random and scaffold splitting, BBBP-GeoPEFT achieves competitive or improved ROC-AUC and accuracy in most experiments while updating only 10.1% of the model parameters.