Molecular Dynamics Simulations of pH-Dependent Ciprofloxacin Adsorption to Na-montmorillonite

Abstract

Ciprofloxacin (CIP) is one of the most widely used and environmentally persistent antibiotic compounds, which is increasingly being found in soils, sediments, and natural waters. Because CIP strongly associates with clay minerals, understanding its molecular-scale adsorption energetics, dynamics, and configurations is essential for predicting environmental retention and mobility. For this purpose, a combination of unbiased molecular dynamics simulations, biased umbrella sampling simulations, alchemical free-energy perturbation was used in this study to obtain the free energy of adsorption, orientational and clustering configurations and interlayer density mapping across controlled hydration states. These simulations were applied to the three pH-dependent environmentally relevant CIP species (CIP⁺, CIP^+/–, CIP^–) interacting with montmorillonite (MMT) in its Na⁺ form, at basal surfaces and within variably hydrated interlayers. All CIP species approached similar center-of-mass separations from the MMT surface but adopt distinct orientational preferences: CIP⁺ binds predominantly flat, CIP^+/– partitions between flat and side-on, and CIP^– samples multiple poses. The potential of mean force profiles revealed that all species adsorb favourably, but with adsorption strengths steeply increasing in the order CIP^– < CIP^+/– < CIP⁺, having standard adsorption free energies of -2.1, -11.8 and -30.0 kJ mol⁻¹, with corresponding sorption Kd values of 6.4, 520, and 1.0×106 cm3/g, respectively. Unbiased open systems simulations further showed that CIP⁺ and CIP^+/- could be intercalated into 2W and 3W hydration states, whereas CIP^- failed to intercalate below 4W. The free energy perturbation simulations revealed the highest hydration free energy for CIP^- across bulk, mesopore, and surface environments, while CIP^+/- and especially CIP⁺ experience increasingly favourable hydration near the clay surface due to enhanced water structuring and electrostatic potential.