Aggregation behavior of sodium caprate under different pH, concentration, and intestinal fluid conditions: a coarse-grained molecular dynamics study comparing Martini 2 and Martini 3

Abstract

Sodium caprate (C10) is an ionizable amphiphile whose self-assembly behavior in aqueous environments is strongly modulated by pH and concentration. Understanding the molecularlevel organization and dynamics of C10 under physiologically relevant solution conditions is important for interpreting its functional behavior in complex media. In this study, we investigated the pH-and concentration-dependent aggregation of C10 in the presence and absence of fasted-state simulated intestinal fluid using coarse-grained molecular dynamics (CG-MD) simulations and compared the results with small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) measurements. Two CG-MD force fields, Martini 2 and Martini 3, were evaluated for their ability to reproduce experimentally observed aggregate structures.Both models captured the expected pH-dependent transition from small micelles at high pH to larger colloidal assemblies at lower pH, with overall good agreement between simulation and experiment. However, clear differences were observed between the force fields: Martini 3 produced SAXS profiles with substantially lower χ² values and exhibited a higher proportion of free monomers and more rapid monomer-aggregate exchange, consistent with theoretical expectations for ionizable fatty acids. By assessing both structural correspondence and molecular-level distributions, this work identifies that Martini 3 coarse-grained model effectively captures the pH-and concentration-dependent self-assembly of C10 and provides insights into its underlying molecular mobility.