Conformational versus Configurational Entropy: Deciphering the Alkyl Chain-Dependent Membrane Attack Mechanism of...

The escalating crisis of antibiotic resistance necessitates alternative antimicrobials like ionic liquid derivatives (ILDs), which target bacterial membranes, yet their structure-activity relationships remain elusive. Here, using all-atom molecular dynamics simulations combined with multiple analytical methods, including principal component analysis, Markov state modeling, and free-energy calculation/decomposition, we elucidate the fundamental mechanisms governing ILD-membrane interactions. Our simulations indicate a universal two-step mechanism involving initial membrane binding, followed by insertion. The ILD alkyl chain length serves as a critical determinant, modulating the conformational properties of monomers versus the configurational properties of aggregates. This structural control creates a thermodynamic dichotomy: monomer-membrane interactions are driven by conformational entropy, whereas aggregate-membrane interactions are governed by configurational entropy within a delicate entropy-enthalpy balance. These mechanistic insights not only reconcile experimental discrepancies but also offer guidance for the rational design. As a proof-of-concept, we demonstrate that membrane attack efficiency can be tuned by modulating alkyl chain rigidity/length or incorporating fullerene C60 into ILD aggregates. Collectively, our work provides a detailed mechanistic understanding to support the rational design of advanced ILD-based antimicrobial agents with tailored membrane-disrupting activities.