title: Predicting proton titration in cationic micelle and bilayer environments.
abstract: Knowledge of the protonation behavior of pH-sensitive molecules in micelles and bilayers has significant implications in consumer product development and biomedical applications. However, the calculation of pKa's in such environments proves challenging using traditional structure-based calculations. Here we apply all-atom constant pH molecular dynamics with explicit ions and titratable water to calculate the pKa of a fatty acid molecule in a micelle of dodecyl trimethylammonium chloride and liquid as well as gel-phase bilayers of diethyl ester dimethylammonium chloride. Interestingly, the pKa of the fatty acid in the gel bilayer is 5.4, 0.4 units lower than that in the analogous liquid bilayer or micelle, despite the fact that the protonated carboxylic group is significantly more desolvated in the gel bilayer. This work illustrates the capability of all-atom constant pH molecular dynamics in capturing the delicate balance in the free energies of desolvation and Coulombic interactions. It also shows the importance of the explicit treatment of ions in sampling the protonation states. The ability to model dynamics of pH-responsive substrates in a bilayer environment is useful for improving fabric care products as well as our understanding of the side effects of anti-inflammatory drugs.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Morrow
authors.affiliation: Computational Chemistry, Modeling and Simulation GCO, Procter and Gamble, Cincinnati, Ohio 45201, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Eike
authors.affiliation: Computational Chemistry, Modeling and Simulation GCO, Procter and Gamble, Cincinnati, Ohio 45201, USA.
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Murch
authors.affiliation: Computational Chemistry, Modeling and Simulation GCO, Procter and Gamble, Cincinnati, Ohio 45201, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Koenig
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA.
authors.forename: Jana K
authors.initials: JK
authors.lastname: Shen
mesh_terms: D002412:Cations / Q000737:chemistry*; D005227:Fatty Acids / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry*; D008823:Micelles; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011522:Protons; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D017186:Titrimetry
chemical_list: D002412:Cations; D005227:Fatty Acids; D008051:Lipid Bilayers; D008823:Micelles; D011522:Protons; D000644:Quaternary Ammonium Compounds; C022806:dodecyltrimethylammonium