Bridging the Evidence-to-Execution Gap:A Reflective Agent for Multi-Objective Peptide Design

Haosen Zhang, Yang Yang

Large language models (LLMs) can reason over scientific literature to devise design strategies, yet fail to reliably implement them for biological sequences. While protein generative models learn sequence patterns, they lack the capacity to incorporate literature evidence for multi-step reflective reasoning, forming an evidence-to-execution gap between scientific reasoning and sequence manipulation. We present EASER (Evidence-Aware Sequence Engineering with Reflection), a reflective agent bridging reasoning and sequence generation via a learned property interface of offline-trained, fixed low-rank matrices. The agent steers a diffusion generator by combining these matrices, proposing intervention hypotheses (anchors, editable positions, control coefficients) grounded in retrieved evidence, sequence context and past results. A Probe-and-Steer mechanism validates interventions and allocates samples according to predicted property responses, with outcome reflection informing subsequent decisions. Evaluated on multi-objective antimicrobial peptide design (optimizing activity, non-hemolysis and non-toxicity), explicit hypothesis formulation delivers better multi-objective performance…