Designing ion pair amphiphiles for biomimetic bilayer formation via the Law of Matching Water Affinity

Background:

Ion pair amphiphiles (IPAs) are emerging as versatile biomimetic molecules capable of self-assembling into bilayer membranes, with applications in drug delivery and nanomaterial design. A critical factor influencing IPA membrane stability is the interaction strength between ionic headgroups. However, predictive frameworks to guide IPA design remain limited.

Methods:

In this study, we applied the Law of Matching Water Affinity (LMWA) as a thermodynamic principle to evaluate and screen IPA head group combinations. Hydration free energies of individual ions and association free energies of ion pairs were calculated using molecular dynamics simulations combined with umbrella sampling. These values were integrated into a volcano plot to identify optimal ion pairs with balanced hydration affinities. The predictions were validated through all-atom molecular dynamics simulations of IPA bilayers.

Significant Findings:

Our results reveal that ion pairs with matched hydration energies form more stable ionic complexes and robust bilayers. Additionally, systems with strong hydrogen bonding and symmetric headgroup geometries exhibited higher mechanical strength, as indicated by compressibility moduli and chain ordering parameters. Conversely, large hydration mismatches or anisotropic headgroups led to micelles or interdigitated structures. This study establishes a predictive LMWA-based framework for rational IPA design, facilitating efficient screening of novel vesicle systems for biomedical applications.