Atomistic Insights into the Chain-Length-Dependent Antifreeze Activity of Oligoprolines.

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.