Hierarchical Molecular Language Models (HMLMs) (2512.00696v1)

Abstract: Cellular signaling networks represent complex information processing systems that have been modeled via traditional mathematical or statistical approaches. However, these methods often struggle to capture context-dependent signaling, pathway cross-talk, and temporal dynamics across multiple biological scales. Here, we introduce hierarchical molecular LLMs (HMLMs), a novel architecture that proposes a molecular network-specific LLM to use in intracellular communication as a specialized molecular language, which includes molecules as tokens, protein interactions, post-translational modifications, and regulatory events modeled as semantic relationships within an adapted transformer architecture. HMLMs employ graph-structured attention mechanisms to accommodate signaling network topology while integrating information across the molecular, pathway, and cellular scales through hierarchical attention patterns. We demonstrate HMLM superiority using a cardiac fibroblast signaling network comprising over 100 molecular species across functional modules connected by regulatory edges. HMLM achieved a mean squared error (MSE) of 0.058 for temporal signaling predictions, representing 30% improvement over graph neural networks (GNNs: 0.083) and 52% improvement over ordinary differential equation models (ODEs: 0.121), with particular advantages under sparse temporal sampling conditions where HMLM maintained MSE = 0.041 with only 4 time-points. The HMLMs offer a foundation for AI-driven biology and medicine with predictable scaling characteristics suitable for interactive applications. By bridging molecular mechanisms with cellular phenotypes through AI-driven molecular language representation, HMLMs provide a powerful paradigm for systems biology that advances precision medicine applications and therapeutic discovery in the era of AI.