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

TL;DR

This study uses molecular dynamics simulations to uncover the atomistic mechanisms behind the nonmonotonic chain-length dependence of antifreeze activity in polyproline, highlighting the roles of molecular conformation and aggregation.

Contribution

It reveals the microscopic factors influencing polyproline's antifreeze activity, challenging the assumption that helix content alone determines efficacy.

Findings

P8 has higher coil conformation content than P15, explaining its superior activity.

P15 exhibits higher aggregation tendency, reducing effective ice surface coverage.

P3's low activity is due to insufficient coverage area on ice surface.

Abstract

Ice recrystallization inhibition (IRI) activity of polymers generally increases with chain length. However, for polyproline (PPro), a highly potent cryoprotectant, the IRI activity varies nonmonotonically with the degree of polymerization (DP), i.e., DP=8 (P8) > DP=15 (P15) > DP=3 (P3). Herein, we employ molecular dynamics simulations to reveal the microscopic mechanism behind this nonmonotonic effect in PPro. Our findings indicate that the population of the PPII helix structure, which increases with DP, is not the primary reason for this effect. Instead, both single-molecule conformation and multi-molecule aggregation play critical roles. At the single-molecule level, PPro exhibits two types of thermodynamically stable conformations:linear (L) and coil (C), with the latter demonstrating enhanced IRI potency due to its stronger hydrophobicity and ice-binding capability. Notably, P8 has a higher content of the C conformation compared to P15, accounting for its superior IRI activity. Aligning with the conventional understandings, P3's lowest activity stems from its excessively small volume/coverage area on the ice surface. At the multi-molecule level, P15 shows a significantly higher tendency to aggregate than P8, which limits the ability of PPro molecules to fully spread at the ice-water interface and reduces their effective coverage of the ice surface, thereby diminishing its effectiveness. And P15's aggregation becomes significantly pronounced at high concentrations, amplifying the nonmonotonic effect. This work provides an atomistic insight into the nonmonotonic relationship between IRI activity and DP in PPro, offering valuable insights for the rational design of novel biocompatible antifreeze polymers.