Self-Assembly and Bilayer–Micelle Transition of Fatty Acids Studied by Replica-Exchange Constant pH Molecular Dynamics

Abstract

Recent interest in the development of surfactant-based nano delivery systems targeting tumor sites has sparked our curiosity to understand the detailed mechanism of the self-assembly and phase transitions of pH-sensitive surfactants. Towards this goal we applied a state-of-the-art simulation technique, continuous constant pH molecular dynamics (CpHMD) with the hybrid-solvent scheme and pH-based replica-exchange protocol, to study de novo self-assembly of 30 and 40 lauric acids, a simple model titratable surfactant. We observed the formation of a gel-state bilayer at low and intermediate pH and a spherical micelle at high pH, with the phase transition starting at 20–30% ionization and completing at 50%. The degree of cooperativity for the transition increases from the 30-mer to the 40-mer. The calculated apparent or bulk pKa value is 7.0 for the 30-mer and 7.5 for the 40-mer. Congruent with experiment, these data demonstrate that CpHMD is capable of accurately modeling large conformational transitions of surfactant systems while allowing simultaneous proton titration of constituent molecules. We suggest that CpHMD simulations may become a useful tool to aid in the design and development of pH-sensitive nanocarriers for a variety of biomedical and technological applications.

Oleic Acid Phase Behavior from Molecular Dynamics Simulations

“…This qualitatively matched results from atomistic constant pH simulations of lauric acid aggregates. 23,24 The basis for the anticooperativity may lie in the above-mentioned trend of each monomer thermodynamically preferring the aggregates composed of the opposite monomers.…”

Recent development and application of constant pH molecular dynamics

“…Most recently, a p K a shift of 0.8 was obtained using the fully explicit-solvent pHREX-CpHMD simulation in the presence of explicit chloride ions (Shen group, unpublished data). This result demonstrates that by incorporating more detailed physics, the all-atom CpHMD is superior in accuracy and can be applied to a wider range of problems such as the coupled dynamics and proton titration of surfactant or lipid bilayers [43, 44]. …”

“…As a generalization of titration of a single fatty acid in micelles, we simulated the self-assembly of 20, 30 and 40 fatty acids in the presence of proton titration of all molecules using hybrid-solvent pHREX-CpHMD [43, 44]. The simulations captured the formation of a micelle at high pH conditions and a bilayer at intermediate and low pH conditions.…”

Responsive self-assemblies based on fatty acids

“…The corresponding p value for the deprotonated form is reduced in comparison to the protonated form approaching values close to 1/2-1/3, which favors the formation of worm-like or spherical micelles. By finely tuning the pH, the ratio between the protonated and deprotonated forms can be adjusted which modifies in turn the packing parameter, the hydrogen bonding and electrostatic interactions [32]. Just by changing the protonation/ionization ratio of the carboxylic acid, a wide range of fatty acid aggregates can be reversibly obtained at the mesoscopic scale.…”