Fig. 5.

(A) The topological model proposes that lipid–peptide shape and charge interactions govern the behavior of LCAMPs. B–E show the specific lipid clustering and geometries responsible for individual PIEs, with lipid geometry shown using block shapes and clustering lipids given as a red outline. The terms of Eq. 1 associated with each PIE are also shown. (A) Peptide binds to the outer leaflet, generating internal membrane strain (σ_G), which controls overall activity (B). Both peptides are more active when clustered with lipids matching their own curvature strain: melittin with conical lipids and m2a with inverse conical lipids. (C) Clustering with lipids matching peptide curvature also governs the carpet mechanism by generating high E_L values and stabilizing the high-curvature lipid–peptide micelles produced. (D) Bursting events for melittin occur when the membrane contains nonclustering conical lipids, which will generate high E_L raft assemblies that cannot react via pore formation (high γ); instead, they cause complete vesicle failure. For m2a, both clustering and nonclustering conical lipids cause bursting. (E) Melittin generates pore activity (low γ) when inverse conical lipids associate with its helical face, while m2a generates pores when clustered with inverse conical lipids. Open pores allow interleaflet material transfer, lowering σ_G and generating a negative feedback system between the rate of LCAMP binding from solution (R_S) and the rate of material flow through open pores (R_P), with three possible cases. (i) R_S > R_P shown in F; there is a continuous increase in σ_G, causing pore opening (blue arrows) until the membrane failure point is reached and the vesicle bursts (red arrows). Examples are shown for system A exposed to m2a (F, Left) and for system C for melittin (F, Right), which display complex leakage dynamics, as several pores open (blue arrows) before a stable leak is established. (ii) R_S = R_P, resulting in a stable leak (G), shown for system C for m2a (G, Left) and melittin (G, Right). (iii) R_P > R_S, decreasing σ_G and favoring pore closure. This renders R_S > R_P, increasing σ_G and reinitiating pore formation. This results in pore opening and closing cycles. H, Left shows a pore-cycling leakage trace (system F; m2a), with its smoothed average (light blue) and fitted single-exponential decay curve (red). (H, Right) The residual between the two curves shown in H, Left (red) compared with the residual for a stable case ii leak (black). The residual shows dynamic cycling between at least two different leakage rates, with intervals between the minima of 1,517, 1,512, and 1,611 s. Consistent cycle spacing is caused by the constant R_S within the microfluidic device.