SearcharxivSearch

arXiv subjects

Minhuan Li

Publications and source records attributed to Minhuan Li.

2 recordsLinked to original sources

MIMIC: A Generative Multimodal Foundation Model for Biomolecules

Biological function emerges from coupled constraints across sequence, structure, regulation, evolution, and cellular context, yet most foundation models in biology are trained within one modality or for a fixed forward task. We present MIMIC, a generative multimodal foundation model trained on our newly curated and aligned dataset, LORE, linking nucleic acid, protein, evolutionary, structural, regulatory, and semantic/contextual modalities within partially observed biomolecular states. MIMIC uses a split-track encoder-decoder architecture to condition on arbitrary subsets of observed modalities and reconstruct or generate missing components of molecular state across the genome, transcriptome, and proteome. Multimodal conditioning consistently improves MIMIC's sequence reconstruction relative to sequence-only inputs, while its learned representations enable state-of-the-art performance on RNA and protein downstream tasks. MIMIC achieves state-of-the-art splicing prediction, and its joint generative formulation enables isoform-aware inference that further improves performance. Beyond prediction, the same generative framework supports constrained design. For RNA, MIMIC identifies corrective edits in a clinically relevant HBB splice-disrupting mutation without reverting it by using evolutionary and structural signals. For proteins, jointly conditioning on shape and surface chemistry of PD-L1 and hACE2 binding sites produces diverse, high-confidence sequences with strong in silico support for target binding. Finally, MIMIC uses experimental context as semantic conditioning to model assay-dependent RNA chemical probing, rather than treating context as a fixed output. Together, these results position MIMIC's aligned multimodal generative modeling as a strong foundation for unifying representation learning, conditional prediction, and constrained biomolecular design within a single model.

cs.AI

Robust Inference-Time Steering of Protein Diffusion Models via Embedding Optimization

A core challenge in structural biophysics is generating biomolecular conformations that are both physically plausible and consistent with experimental measurements. While sequence-to-structure diffusion models provide powerful priors, posterior sampling methods steer generation by perturbing atomic coordinates with gradients from experimental likelihoods. However, when the target lies in a low-density region of the prior, these methods require aggressive upweighting of the likelihood that can destabilize sampling and be sensitive to hyperparameters. We propose EmbedOpt, an inference-time steering framework that introduces an orthogonal optimization axis: rather than performing posterior sampling under a fixed prior, EmbedOpt directly optimizes the prior by updating the model's conditional embedding. This embedding space encodes rich coevolutionary signals, so optimizing it shifts the structural prior to align with experimental constraints. Empirically, EmbedOpt matches coordinate-based posterior sampling baselines on sparse distance constraints and outperforms them on cryo-electron microscopy map fitting, including real, noisy experimental ones. Furthermore, EmbedOpt's smooth optimization behavior yields robustness to hyperparameters spanning two orders of magnitude and enables comparable performance with fewer diffusion steps. Code is available at https://github.com/rs-station/embedopt.

cs.LG