Interaction between K+ channel gate modifier hanatoxin and lipid bilayer membranes analyzed by molecular dynamics simulation

Abstract

Hanatoxin (HaTx) is an ellipsoidal-shaped peptide that binds to the voltage sensor of voltage-dependent channels. Of physicochemical interest, HaTx has a "ring" of charged residues around its periphery and a hydrophobic protrusion. It has previously been postulated that HaTx binds to and functions on the surface of membranes, but a recent fluorescent-quenching study has implied a fairly deep positioning of HaTx in the lipid bilayer membrane. We carried out numerous molecular dynamic simulations of HaTx1, a well-studied variant of HaTx, in fully hydrated phospholipid bilayers. The system reproduced the surface-binding mode of HaTx1, in which HaTx1 resided in the extracellular side (outer) of the water/membrane interface with the hydrophobic patch of HaTx1 facing the membrane interior. On the other hand, analyses with various parameter settings suggested that the surface-binding mode was unstable because of the substantial attractive electrostatic force between HaTx1 and the lipid head groups of the inner (opposite) leaflet. Compared with this electrostatic force, the energetic cost for membrane deformation involving meniscus formation appeared to be small. In an attempt to interpret the quenching data, we consider the possibility of dimpling (meniscus formation) that brings HaTx1 inward (only ~0.7-0.8 nm above the bilayer center), while accounting for the flexibility of both leaflets of the membrane and the long-range interaction between positively charged residues of the membrane-bound peptide and the polar head groups of the opposite leaflet of the membrane. It is suggested that molecular dynamics simulations taking into account the flexibility of the membrane surface is potentially useful in interpreting the fluorescence-quenching data.

Effect of Gating Modifier Toxins on Membrane Thickness: Implications for Toxin Effect on Gramicidin and Mechanosensitive Channels

“…Several molecular dynamics (MD) simulation studies have been carried out to understand the binding mechanism of gating modifier toxins in model membranes [33,34,35,36,37,38]. In these studies, the toxins are frequently embedded into the lipid bilayer at different depths at the start of the simulations to probe the most preferred position of toxin binding.…”

Bioinspired Mechanism for the Translocation of Peptide through the Cell Membrane

“…However, the changes considered were toward negative 1820 in accordance with the Stalk model, which is a well-accepted model for the cell fusion or fission process generated by antimicrobial peptides (AMPs). 19,20 As shown in Figure S1d, 24 this process can be applied to the multilayered lamellar L¡ phase, and cell fusion or fission could occur between the two bilayers (Graphical Abstract). Induction of negative curvature or increase in CPP caused by PTD or AMPs for multi-bilayer would induce membrane deformation according to the Stalk model.…”

A model for modulation of neuronal synchronization by D4 dopamine receptor-mediated phospholipid methylation

“…These changes modulate conformational changes between the channel conducting and nonconducting states (Venturoli et al 2005;Cascio 2005). Recent theoretical (Lee 2006;Sperotto et al 2006) and experimental studies have examined the influence of bilayer composition on ion channel functions, in particular on voltage-dependent potassium channels (Nishizawa and Nishizawa 2006;Lee et al 2005;Tillman and Cascio 2003;Schmidt et al 2006;Bond and Sansom 2007), including lipid-induced switching between different types of potassium channels (Oliver et al 2004). Simulation studies predict that proteins may tilt and bend to adapt to changes in lipid bilayer due to hydrophobic mismatch within nanoseconds (Venturoli et al 2005), yielding changes in protein activity (Lee 2003).…”