PepLLM: ESM-Guided Llama for Structured Protein-Peptide Binding Interface Analysis

Abstract:Protein-peptide interactions are central to cellular regulation and peptide-based drug discovery, yet existing computational methods mainly focus on interaction classification, binding-site prediction, or peptide binder generation. These formulations provide limited insight into the physicochemical mechanisms that determine how a peptide binds to a protein. In this work, we introduce \textbf{PepLLM}, an instruction-tuned framework for structured protein-peptide interface understanding. Given protein-peptide sequences, PepLLM generates a machine-readable JSON annotation describing multiple interface properties, including peptide burial state, hydrogen-bond density, salt-bridge presence, hotspot residues, hydrophobicity, and electrostatic complementarity. To support this task, we construct a new protein-peptide interface dataset by integrating structural interface analysis, solvent-accessible surface area computation, hydrophobic burial estimation, electrostatic potential calculation, and redundancy-aware data splitting. PepLLM connects a pretrained ESM encoder with a LLaMA decoder through a nonlinear modality adapter. The adapted ESM residue embeddings are injected into the LLaMA prompt as continuous soft tokens via placeholder-token replacement, enabling the decoder to generate structured interface annotations under instruction tuning. By moving beyond single-label prediction toward multi-property and mechanism-aware generation, PepLLM establishes a new task and modeling paradigm for interpretable protein-peptide interface analysis.

Biomolecules (q-bio.BM); Artificial Intelligence (cs.AI); Machine Learning (cs.LG)

arXiv:2608.21367 [q-bio.BM]

(or arXiv:2608.21367v1 [q-bio.BM] for this version)

https://doi.org/10.48550/arXiv.2608.21367 Focus to learn more arXiv-issued DOI via DataCite

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