Optimal Hydrophobicity and Reorientation of Amphiphilic Peptides Translocating through Membrane

Abstract

Cell-penetrating and some antimicrobial peptides can translocate across lipid bilayers without disrupting the membrane structure. However, the molecular properties required for efficient translocation are not fully understood. We employed the Metropolis Monte Carlo method together with coarse-grained models to systematically investigate free-energy landscapes associated with the translocation of secondary amphiphilic peptides. We studied α-helical peptides with different length, amphiphilicity, and distribution of hydrophobic content and found a common translocation path consisting of adsorption, tilting, and insertion. In the adsorbed state, the peptides are parallel to the membrane plane, whereas, in the inserted state, the peptides are perpendicular to the membrane. Our simulations demonstrate that, for all tested peptides, there is an optimal ratio of hydrophilic/hydrophobic content at which the peptides cross the membrane the easiest. Moreover, we show that the hydrophobicity of peptide termini has an important effect on the translocation barrier. These results provide general guidance to optimize peptides for use as carriers of molecular cargos or as therapeutics themselves.

SPA: a peptide antagonist that acts as a cell-penetrating peptide for drug delivery

“…To this end, several strategies have been employed successfully, such as conformational constraints, the systematic alteration of physicochemical properties and the development of activatable CPPs (Copolovici et al, 2014;Wang et al, 2014;Peraro & Kritzer, 2018). With broad and deep studies on the structure-activity relationships of CPPs, hydrophobicity has been deemed as an important factor for enhancing the uptake efficiency of CPPs (Gupta et al, 2011;Jones & Sayers, 2012;Kabelka & Vacha, 2018). In our previous work, hydrophobic antitumor drug CPT could significantly increase the membrane-lytic activity and cell-penetrating activity of TAT after the attachment to the N-terminus of TAT (Song et al, 2015).…”

Magainin 2 and PGLa in Bacterial Membrane Mimics I: Peptide-Peptide and Lipid-Peptide Interactions

“…The dependence of MG2a-mediated PGLa insertion into bilayers was attributed to the intrinsic lipid curvature, which leads to a tight packing of the bilayer's polar-apolar interface in the case of cone-shaped lipids such as POPE and increases the energy barrier for peptide translocation (5,14). Recently, this was refined by also considering details of hydrocarbon chain configurations (13).…”

Lactoferricins access the cytosol of Escherichia coli within few seconds

“…This might be also a consequence of the rather short amino acid sequence of the lactoferricin derivatives, implying a too small length (~ 1 nm) to span the whole membrane thickness (3 – 4 nm). In turn, the highly flexible secondary structure and an amphipathic momentum being aligned along the peptide’s backbone ( Zorko et al, 2009 ; Zweytick et al, 2011, 2014 ) should allow LF11-324 and LF11-215 to translocate membranes at higher rates than observed for linear peptides ( Ulmschneider, 2017 ; Kabelka and Vácha, 2018 ). Note that peptide translocation can also lead to transient membrane leakage events ( Ulmschneider, 2017 ), even with negligible AMP-induced lipid flip-flop ( Marx et al, 2021a ).…”