What Transfers Across Protein Pockets? Experience Reuse in Molecular Optimization for Agentic Structure-Based Drug Design

Zaifei Yang, Weiyu Chen, Yaqing Wang, James Kwok

LLM agents optimize a ligand in a protein pocket by editing it step by step and docking each edit. Recent agents first spend extra dockings probing the complex with controlled edits; guidance induced from these probes is reported to help more than the chemical knowledge the model already carries. The probes are then discarded with the instance that produced them, so the obvious next step is to keep them in an experience base, letting a new pocket inherit what earlier ones already paid for. Such a base is read through a \emph{key}: the record properties under which past edits are pooled and a new one is looked up. Using the full log of one such run over the CrossDocked2020 test-set pockets, we ask whether its keys recur on a pocket the base has never seen and still separate improving from worsening edits. \crchange{Using} the contacts at the site being edited, the action, and the round as \crchange{a} key, the base separates them sharply. Within our analysis, this separation is largely explained by how much the edit changed the molecule's size, the action, and the round, none of which describes the target. That is not because the target is irrelevant: naming it outright separates…