Why Static SAR Fails for Antimicrobial Peptides From an Ensemble and Free‐Energy Landscape Perspective?

ABSTRACT Classical structure–activity relationships (SAR) have limited predictive power for antimicrobial peptides (AMPs) because they assume fixed structures, single mechanisms, and independent physicochemical descriptors. In practice, AMP activity arises from dynamic, multistate ensembles that reorganize with environment, concentration, and membrane context. Here, we propose that the AMP function is best described using an ensemble‐based chemical framework grounded in free‐energy landscapes and interfacial thermodynamics. Peptide sequences encode distributions of chemically accessible states rather than unique bioactive conformations, while environmental variables selectively redistribute these populations across interfacial, inserted, and oligomeric regimes. Biological outcomes such as membrane disruption, intracellular access, and selectivity emerge as conditional consequences of state population shifts rather than intrinsic sequence‐encoded mechanisms. This perspective provides a chemically grounded alternative to static SAR and suggests that effective AMP design should focus on controlling ensemble redistribution under realistic interfacial environments.