Fluorinated Alcohols’ Effects on Lipid Bilayer Properties

Abstract

Fluorinated alcohols (fluoroalcohols) have physicochemical properties that make them excellent solvents of peptides, proteins, and other compounds. Like other alcohols, fluoroalcohols also alter membrane protein function and lipid bilayer properties and stability. Thus, the questions arise: how potent are fluoroalcohols as lipid-bilayer-perturbing compounds, could small residual amounts that remain after adding compounds dissolved in fluoroalcohols alter lipid bilayer properties sufficiently to affect membranes and membrane protein function, and do they behave like other alcohols? To address these questions, we used a gramicidin-based fluorescence assay to determine the bilayer-modifying potency of selected fluoroalcohols: trifluoroethanol (TFE), HFIP, and perfluoro-tert-butanol (PFTB). These fluoroalcohols alter bilayer properties in the low (PFTB) to high (TFE) mM range. Using the same assay, we determined the bilayer partitioning of the alcohols. When referenced to the aqueous concentrations, the fluoroalcohols are more bilayer perturbing than their nonfluorinated counterparts, with the largest fluoroalcohol, PFTB, being the most potent and the smallest, TFE, the least. When referenced to the mole fractions in the membrane, however, the fluoroalcohols have equal or lesser bilayer-perturbing potency than their nonfluorinated counterparts, with TFE being more bilayer perturbing than PFTB. We compared the fluoroalcohols' molecular level bilayer interactions using atomistic molecular dynamics simulations and showed how, at higher concentrations, they can cause bilayer breakdown using absorbance measurements and P nuclear magnetic resonance.

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“…The results in Fig. 5 (A and B) suggest that the ADs’ bilayer-modifying effects depend on their mole fraction in bilayer, with relatively little dependence on their molecular structure, similar to previous studies with aliphatic alcohols (Ingólfsson and Andersen, 2011; Zhang et al, 2018). That cLogD 7 provides such poor predictive ability (Fig.…”

“…The slopes of the fits to the log K 1 −log( D AD ) and clogP−log( D AD ) relations are indeed indistinguishable from −1, meaning that the relative bilayer-modifying potency of different ADs depends primarily on their relative partition coefficients into the bilayer. This conclusion is consistent with the results of Ingolfsson and Andersen (2011) and Zhang et al (2018) on normal and fluorinated alcohols but in contrast with the results on a series of analogues of the snail toxin 6-bromo-2-mercaptotryptamine dimer, which showed no correlation between drug partitioning into the bilayer and their bilayer-modifying potency.…”

How Alcoholic Disinfectants Affect Coronavirus Model Membranes: Membrane Fluidity, Permeability, and Disintegration

“… 2 , 3 Molecular simulations also confirm that small amphiphilic molecules dissolve in the membrane lipid and cause structural changes, including modification of bilayer packing and influencing the lipid acyl chain order, the phase transition temperature, and corresponding self-assembling properties of bilayer vesicles. 4 , 5 Such alcohol-induced structural changes in bilayers alter membrane function, influence the shape and stability of the cells and liposomes, and affect the conformational state of transmembrane proteins and their functions. As the membrane acts as a barrier to the passage of small molecules through it, the role and function of alcohols in the structural changes in lipid membranes depend on the permeability of the membrane to alcohols.…”

Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides

“…Examples for this strategy represent the synthesis of d-Ala 17 -phGnRH(14-36) (Milton and Milton, 1990) or model "difficult sequences" (Yamashiro et al, 1976). Fluorinated alcohols are also known as effective solvents for hydrophobic peptides, which can be used during analytics and purification, namely key steps two and three, of the chemical production (Figure 1; Tiburu et al, 2009;Bondarenko et al, 2010;Zhang et al, 2018). The reason for that is that TFE or HFIP mimic the natural environment of the cell membrane thus mediate the dissolution of membrane-associated peptides.…”