title: Phase separation behavior of mixed lipid systems at neutral and low pH: coarse-grained simulations with DMD/LIME.
abstract: We extend LIME, an intermediate resolution, implicit solvent model for phospholipids previously used in discontinuous molecular dynamics simulations of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer formation at 325 K, to the description of the geometry and energetics of 1,2-distearoyl-sn-glycero-3-phospho-L-serine (DSPS) and 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine (21PC) and mixtures thereof at both neutral and low pH at 310 K. A multiscale modeling approach is used to calculate the LIME parameters from atomistic simulation data on a mixed DPPC/DSPS system at different pH values. In the model, 17 coarse-grained sites represent DSPS and 18 coarse-grained sites represent 21PC. Each of these coarse-grained sites is classified as 1 of 9 types. LIME/DMD simulations of equimolar bilayers show the following: (1) 21PC/DSPS bilayers with and without surface area restrictions separate faster at low pH than at neutral pH, (2) 21PC/DSPS systems separate at approximately the same rate regardless of whether they are subjected to surface area restrictions, and (3) bilayers with a molar ratio of 9:1 (21PC:DSPS) phase separate to form heterogeneous domains faster at low pH than at neutral pH. Our results are consistent with experimental findings of Sofou and co-workers (Bandekar et al. Mol. Pharmaceutics, 2013, 10, 152-160; Karve et al. Biomaterials, 2010, 31, 4409-4416) that more doxorubicin is released from 21PC/DSPS liposomes at low pH than at neutral pH, presumably because greater phase separation is achieved at low pH than at neutral pH. These are the first molecular-level simulations of the phase separation in mixed lipid bilayers induced by a change in pH.
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University , Engineering Building I, 911 Partners Way, Raleigh, North Carolina 27695-7905, United States.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Curtis
authors.forename: Xingqing
authors.initials: X
authors.lastname: Xiao
authors.forename: Stavroula
authors.initials: S
authors.lastname: Sofou
authors.forename: Carol K
authors.initials: CK
authors.lastname: Hall
mesh_terms: D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry*; D010768:Phosphoserine / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics
chemical_list: D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010768:Phosphoserine; C010942:1,2-distearoyllecithin