Conformation–Activity Relationship of Amphiphilic l‑Alanine and l‑Lysine Block Copolymers: From Dynamic Ice-Inhibition Mechanisms to Rational Molecular Design

We establish a direct relationship between conformational flexibility and ice-inhibition activity in an amphiphilic block copolymer of l-alanine and l-lysine (PA-b-PK), revealing that rationally restricting conformational variation is a key strategy for enhancing antifreeze performance. All-atom molecular dynamics simulations show that PA-b-PK adopts a dynamic α-helix/coil hybrid structure in solution, a preference that becomes more pronounced near the freezing point of water. Consistent with experiments, PA-b-PK in simulations preferentially binds to both primary prismatic and basal ice planes, but an excessive conformational change upon adsorption weakens its ice-growth inhibition ability. Guided by this insight, we designed a cyclized PA-b-PK variant to restrict flexibility. This locked architecture promotes a vertically segregated amphiphilic structure at the ice–water interface, resulting in greater ice-surface coverage and more effective ice-growth suppression than linear PA-b-PK. These computational findings validate a conformation-directed design approach, offering a theoretical framework for developing potent cryoprotective materials.