LAUSR

Oligoproline is a simple yet highly potent cryoprotectant, but the molecular basis underlying its nonmonotonic ice recrystallization inhibition (IRI) activity depending on the degree of polymerization (DP)particularly the superior performance of DP = 8 (P8) over longer (e.g., P15) oligomersremains elusive. Using molecular dynamics simulations, we show that the IRI activity originates from the combined effect of single-molecule conformation and multimolecule aggregation. P8 outperforms P15 primarily due to its higher proportion of the random coil (C) conformation, which effectively enhances ice-binding ability and resistance to ice engulfment than the linear (L) conformation with perfect PPII helix. Moreover, at high concentrations (>40 mg/mL), P15 tends to form soluble amorphous aggregates, reducing its effective coverage on the ice surface and thereby further diminishing its IRI efficiency. These findings provide atomistic insight into the structure–activity relationship of oligoprolines and offer a framework for understanding similar nonmonotonic effects in other antifreeze polymers.