Zhi John Lu

Letian Gao, Zhi John Lu

RNA plays a pivotal role in diverse biological processes, ranging from gene regulation to catalysis. Recent advances in RNA design, such as RfamGen, Ribodiffusion and RDesign, have demonstrated promising results, with successful designs of functional sequences. However, RNA design remains challenging due to the inherent flexibility of RNA molecules and the scarcity of experimental data on tertiary and secondary structures compared to proteins. These limitations highlight the need for a more universal and comprehensive approach to RNA design that integrates diverse annotation information at the sequence level. To address these challenges, we propose RNACG (RNA Conditional Generator), a universal framework for RNA sequence design based on flow matching. RNACG supports diverse conditional inputs, including structural, functional, and family-specific annotations, and offers a modular design that allows users to customize the encoding network for specific tasks. By unifying sequence generation under a single framework, RNACG enables the integration of multiple RNA design paradigms, from family-specific generation to tertiary structure inverse folding.

Jiahao Chen, Letian Gao, Yanhao Zhu et al.

Recent advances in generative modeling have enabled significant progress in structure-based drug design (SBDD). Existing methods typically condition molecule generation on empty binding pockets from holo complexes, overlooking informative components such as the filler (ligands and solvent). Here, we leverage low-resolution electron density (ED) derived from the filler as a physically grounded condition for \textit{de novo} drug design. We consider two types of ED, calculated and cryo-EM/X-ray, obtainable from computational or experimental sources, supporting unified pre-training and experimental integration. Compared with rigid pocket representations, experimental ED naturally captures conformational flexibility and provides a more faithful description of the binding environment. Based on this, we introduce EDMolGPT, a decoder-only autoregressive framework that generates molecules from low-resolution ED point clouds. By grounding generation in physically meaningful density signals, EDMolGPT mitigates structural bias and produces molecules with 3D conformations. Evaluations on 101 biological targets verify the effectiveness. Our project page: https://jiahaochen1.github.io/EDMolGPT_Page/.