A lipocentric view of peptide-induced pores

Abstract

Although lipid membranes serve as effective sealing barriers for the passage of most polar solutes, nonmediated leakage is not completely improbable. A high activation energy normally keeps unassisted bilayer permeation at a very low frequency, but lipids are able to self-organize as pores even in peptide-free and protein-free membranes. The probability of leakage phenomena increases under conditions such as phase coexistence, external stress or perturbation associated to binding of nonlipidic molecules. Here, we argue that pore formation can be viewed as an intrinsic property of lipid bilayers, with strong similarities in the structure and mechanism between pores formed with participation of peptides, lipidic pores induced by different types of stress, and spontaneous transient bilayer defects driven by thermal fluctuations. Within such a lipocentric framework, amphipathic peptides are best described as pore-inducing rather than pore-forming elements. Active peptides bound to membranes can be understood as a source of internal surface tension which facilitates pore formation by diminishing the high activation energy barrier. This first or immediate action of the peptide has some resemblance to catalysis. However, the presence of membrane-active peptides has the additional effect of displacing the equilibrium towards the pore-open state, which is then maintained over long times, and reducing the size of initial individual pores. Thus, pore-inducing peptides, regardless of their sequence and oligomeric organization, can be assigned a double role of increasing the probability of pore formation in membranes to high levels as well as stabilizing these pores after they appear.

Experimental Estimation of Membrane Tension Induced by Osmotic Pressure

“…It is generally considered that thermal fluctuation in the lateral density of a lipid membrane induces a prepore (27). According to the classical theory of tension-induced pore formation (36)(37)(38), once a prepore with radius r p is formed in the membrane, the total free energy of the system changes by an additional free-energy component (called the free energy of a prepore, U (r p , s t )) consisting of two terms: one term (Àpr p 2 s t ) is associated with lateral tension (s t ) and favors expansion of the prepore, and the other term (2pr p G) is associated with the line tension (G) of the prepore edge and favors prepore closure. The free energy of a prepore, U (r p , s t ), can therefore be expressed as (Fig.…”

Resolving the kinetics of lipid, protein and peptide diffusion in membranes

“…Slower translocation rates have been reported for integral transmembrane peptides (Kol et al, 2003;Kol et al 2001). It should be noted that peptide-induced translocation is not a general phenomenon, particularly for transmembrane peptides (Marsh, 2008 Fuertes et al, 2011;Salnikov and Bechinger, 2011;Anglin et al, 2009;Gurtovenko and Vattulainen, 2007;Cho et al, 2007).…”

“…Pore formation occurs above a critical ratio of peptide to lipid (P/L*), and as a consequence the rate of flip-flop (and pore formation) is not linear with respect to peptide concentration (Fuertes et al, 2011, Huang, 2006. ii.…”

“…This mechanism has been proposed for a number of peptides, including alamethicin (Pabst et al, 2007), gramicidin A (Anglin et al, 2007), and the WALP23 peptide described above (Anglin et al, 2009). As the membrane is a dynamic structure, localized defects generated by thermal fluctuations will occur spontaneously and translocation through these is likely to be responsible for the background rate of translocation in the absence of peptides or other perturbing agents (Fuertes et al, 2011).…”

“…Studies of this nature are infrequent; the majority of cases focus measurements on either peptide or lipid properties, with phenomena such as marker release usually implicitly interpreted in terms of peptide models. Recently, a more lipid-centric viewpoint has been called for that is more in keeping with the kinetics of poration phenomena (Fuertes et al, 2011). Before considering more lipid inclusive models, it is useful to consider alternative models for interpreting data from marker release experiments.…”