Title: Clarifying Multimodal Biomolecular Co-Design Through Intrinsic Geodesic Coupling

Abstract: Proteins and small-molecule ligands are fundamental to biological systems, emerging from the intricate relationship between their amino acid sequences and three-dimensional conformations. While recent generative models for biomolecular co-design attempt to replicate this relationship by jointly modeling these coupled modalities, current methodologies typically rely on a parallel execution of marginal generative processes. This approach implicitly mandates a fixed, synchronous coupling. We posit that a crucial yet underappreciated variable is the temporal coupling of these marginal processes during both training and generation. Improper coupling strategies can lead to high-variance supervision and inconsistent intermediate states, thereby compromising modality consistency. To resolve this issue, we present GeoCoupling, a comprehensive framework designed to optimize temporal alignments between heterogeneous modalities. Our empirical evaluations, spanning unconditional protein design and structure-based drug design, reveal that the learned couplings consistently surpass both synchronous and randomly coupled baselines, resulting in biomolecules that exhibit enhanced physical validity and diversity.

Source: arXiv Generated at: 2026-06-02 00:00:00 UTC