Demystifying Multimodal Biomolecular Co-design With Intrinsic Geodesic Coupling

Keyue Qiu; Xintong Wang; Zhilong Zhang; Hao Zhou; Wei-Ying Ma

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arXiv · 2606.01628

Demystifying Multimodal Biomolecular Co-design With Intrinsic Geodesic Coupling

Keyue Qiu·Xintong Wang·Zhilong Zhang·Hao Zhou·Wei-Ying Ma

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Abstract

Biomolecules such as proteins and small-molecule ligands play a central role in biological systems, arising from the tight interplay between sequence and three-dimensional structure. Recent generative models for biomolecular co-design aim to capture this interplay by jointly modeling coupled modalities. However, existing approaches largely adopt a parallel execution of marginal generative processes, implicitly enforcing fixed synchronous coupling. We argue that a critical but overlooked degree of freedom lies in how these marginal processes are temporally coupled during training and generation, where inappropriate coupling can introduce high-variance supervision and inconsistent intermediate states, affecting modality consistency. To address this, we introduce GeoCoupling, a systematic framework that optimizes for temporal couplings between heterogeneous modalities. Empirical results across structure-based drug design and unconditional protein design demonstrate the learned couplings consistently outperform synchronous and randomly coupled baselines, yielding biomolecules with improved physical validity and diversity.

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Keyue Qiu, Xintong Wang, Zhilong Zhang, Hao Zhou, Wei-Ying Ma. 2026-06-01. Demystifying Multimodal Biomolecular Co-design With Intrinsic Geodesic Coupling. https://arxiv.org/abs/2606.01628

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