Modeling the partitioning of amphiphilic molecules and co-solvents in biomembranes

Abstract

Amphiphilic co-solvents can have a significant impact on the structure, organization and physical properties of lipid bilayers. Describing the mutual impact of partitioning and induced structure changes is therefore a crucial consideration for a range of topics such as anesthesia and other pharmacokinetic effects, as well as microbial solvent tolerance in the production of biofuels and other fermentation products, where molecules such as ethanol, butanol or acetic acid might be generated. Small-angle neutron scattering (SANS) is a key method for studying lipid and polymer bilayer structures, with many models for extracting bilayer structure (thickness, area per lipid etc.) from scattering data in use today. However, the molecular details of co-solvent partitioning are conflated with induced changes to bilayer structure, making interpretation and modeling of the scattering curves a challenge with the existing set of models. To address this, a model of a bilayer structure is presented which invokes a two-term partition constant accounting for the localization of the co-solvent within the bilayer. This model was validated using a series of SANS measurements of lipid vesicles in the presence of the co-solvent tetrahydrofuran (THF), showing several strategies of how to deploy the two-parameter partition constant model to describe scattering data and extract both structure and partitioning information from the data. Molecular dynamics simulations are then used to evaluate assumptions of the model, provide additional molecular scale details and illustrate its complementary nature to the data fitting procedure. This approach results in estimates of the partition coefficient for THF in 1,2-dimyristoyl-sn-glycero-3-phosphocholine at 35°C, along with an estimate of the fraction of THF residing in the hydrophobic core of the membrane. The authors envision that this model will be applicable to a wide range of other bilayer/amphiphile interactions and provide the associated code needed to implement this model as a fitting algorithm for scattering data in the SasView suite.

Amphiphilic Co-Solvents Modulate the Structure of Membrane Domains

“…We observe the mismatch increasing from 4.5 to 6.3 Å for the D1 composition and from 9.9 to 11.2 Å in the D7 composition upon the addition of EtOH at 0.06% (wt/wt). The trade-off of the two-parameter partition coefficient approach is a slightly lower quality of fit when compared to a previously used asymmetric model, though the hydrophobic thickness estimates obtained from either approach are similar. A comparison is included in the Supporting Information, Figure S1, and it is important to reiterate that the two-parameter partition coefficient approach allowed us to extract bilayer thickness measurements that are directly linked to a physical model rather than a phenomenological estimate of thickness.…”

“…This can be defined quantitatively using a two-parameter partition coefficient approach, parallel to the analysis of the SANS data. 30 We can define an overall partition coefficient, K p , and a distribution parameter, P s , which specifies where EtOH is found (0 to 1 range, with 0 indicating EtOH in the headgroup region or 1 indicating all the EtOH in the hydrophobic tail region). As detailed in Figure 5 and Table 1, we calculated the partition coefficients from the MD simulations, finding values of 0.34 for D1 Ld, 0.41 for D7 Ld, 0.11 for D1 Lo, and 0.11 for D7 Lo.…”

“…Figure summarizes the experimentally determined transverse structure of the individual phases. We used the two-parameter partition coefficient model to extract the structure from the SANS data, shown in Figure S1. This model explicitly invokes molecular volumes and scattering lengths in a symmetric three-slab model, introducing the partition coefficient to account for the EtOH molecules which enter the headgroup and hydrophobic core of the bilayer .…”

“…We used the two-parameter partition coefficient model to extract the structure from the SANS data, shown in Figure S1. This model explicitly invokes molecular volumes and scattering lengths in a symmetric three-slab model, introducing the partition coefficient to account for the EtOH molecules which enter the headgroup and hydrophobic core of the bilayer . Treating the data this way allows us to account for the partitioning, K p , and localization, P s , of the co-solvent as well as extract an explicit structural description, estimating the water content, n w ; area per lipid, APL; thickness of the hydrophobic core, 2 D c ; and thickness of the lipid head group, D H .…”

“…SANS is used to examine the transverse structure of the co-existing phases. Here, we report the structure as determined by the two-parameter partition coefficient model for the individual Ld and Lo phases of the (A) D1 and (B) D7 compositions, both with and without the presence of EtOH at 6% (wt/wt). (C) We utilize this structural picture to estimate (D) the hydrophobic thickness, t** , from which we can assess (E) the hydrophobic thickness mismatch, 2δ, between the phases.…”