Neuronal morphology is essential for studying brain functioning and understanding neurodegenerative disorders. As acquiring real-world morphology data is expensive, computational approaches for morphology generation have been studied. Traditional methods heavily rely on expert-set rules and parameter tuning, making it difficult to generalize across different types of morphologies. Recently, MorphVAE was introduced as the sole learning-based method, but its generated morphologies lack plausibility, i.e., they do not appear realistic enough and most of the generated samples are topologically invalid. To fill this gap, this paper proposes MorphGrower, which mimicks the neuron natural growth mechanism for generation. Specifically, MorphGrower generates morphologies layer by layer, with each subsequent layer conditioned on the previously generated structure. During each layer generation, MorphGrower utilizes a pair of sibling branches as the basic generation block and generates branch pairs synchronously. This approach ensures topological validity and allows for fine-grained generation, thereby enhancing the realism of the final generated morphologies. Results on four real-world datasets demonstrate that MorphGrower outperforms MorphVAE by a notable margin. Importantly, the electrophysiological response simulation demonstrates the plausibility of our generated samples from a neuroscience perspective. Our code is available at https://github.com/Thinklab-SJTU/MorphGrower.

Predicting the binding sites of target proteins plays a fundamental role in drug discovery. Most existing deep-learning methods consider a protein as a 3D image by spatially clustering its atoms into voxels and then feed the voxelized protein into a 3D CNN for prediction. However, the CNN-based methods encounter several critical issues: 1) defective in representing irregular protein structures; 2) sensitive to rotations; 3) insufficient to characterize the protein surface; 4) unaware of protein size shift. To address the above issues, this work proposes EquiPocket, an E(3)-equivariant Graph Neural Network (GNN) for binding site prediction, which comprises three modules: the first one to extract local geometric information for each surface atom, the second one to model both the chemical and spatial structure of protein and the last one to capture the geometry of the surface via equivariant message passing over the surface atoms. We further propose a dense attention output layer to alleviate the effect incurred by variable protein size. Extensive experiments on several representative benchmarks demonstrate the superiority of our framework to the state-of-the-art methods.

Although recent advances in higher-order Graph Neural Networks (GNNs) improve the theoretical expressiveness and molecular property predictive performance, they often fall short of the empirical performance of models that explicitly use fragment information as inductive bias. However, for these approaches, there exists no theoretic expressivity study. In this work, we propose the *Fragment-WL* test, an extension to the well-known Weisfeiler & Leman (WL) test, which enables the theoretic analysis of these fragment-biased GNNs. Building on the insights gained from the Fragment-WL test, we develop a new GNN architecture and a fragmentation with infinite vocabulary that significantly boosts expressiveness. We show the effectiveness of our model on synthetic and real-world data where we outperform all GNNs on Peptides and have $12$% lower error than all GNNs on ZINC and $34$% lower error than other fragment-biased models. Furthermore, we show that our model exhibits superior generalization capabilities compared to the latest transformer-based architectures, positioning it as a robust solution for a range of molecular modeling tasks.

Molecule synthesis through machine learning is one of the fundamental problems in drug discovery. Current data-driven strategies employ one-step retrosynthesis models and search algorithms to predict synthetic routes in a top-bottom manner. Despite their effective performance, these strategies face limitations in the molecule synthetic route generation due to a greedy selection of the next molecule set without any lookahead. Furthermore, existing strategies cannot control the generation of synthetic routes based on possible criteria such as material costs, yields, and step count. In this work, we propose a general and principled framework via conditional residual energy-based models (EBMs), that focus on the quality of the entire synthetic route based on the specific criteria. By incorporating an additional energy-based function into our probabilistic model, our proposed algorithm can enhance the quality of the most probable synthetic routes (with higher probabilities) generated by various strategies in a plug-and-play fashion. Extensive experiments demonstrate that our framework can consistently boost performance across various strategies and outperforms previous state-of-the-art top-1 accuracy by a margin of 2.5%. Code is available at https://github.com/SongtaoLiu0823/CREBM.