Supramolecular cooperativity through the lens of enhanced sampling molecular dynamics

Abstract

Supramolecular polymers are dynamic aggregates whose properties arise from their constitutive bonds, based on reversible, non-covalent interactions. A central aspect in the design and function of these materials is the cooperativity of polymerization, by which the addition of monomers becomes increasingly favorable as the polymer grows. Cooperativity strongly influences both the structure and collective behavior of supramolecular materials, with significant implications for their properties. Understanding the origins and consequences of cooperativity is crucial for the rational design of new functional supramolecular polymer systems. Herein, we systematically explore the cooperativity of supramolecular polymer systems via Molecular Dynamics simulations, powered by On-the-fly Probability Enhanced Sampling, to accurately characterize the free energy landscape associated with polymerization. We validate our approach via ad hoc, minimalistic coarse-grained models of cooperative and non-cooperative self-assembling monomers. We then apply our analysis to ureidopyrimidinone (UPy) supramolecular polymers, widely used in biohydrogel design. Our work provides detailed insights into the UPy polymerization process and how cooperativity can emerge from the hierarchical character of its supramolecular structure. The results underscore the importance of an extensive molecular simulation approach to obtain a quantitative characterization of the self-assembly thermodynamics, which is crucial to guide the rational development of next-generation supramolecular materials.