Modeling arginine peptides adsorption to membrane pores: a molecular theory approach

Abstract

Experiments and molecular simulations suggest that the membrane translocation mechanism of arginine-rich cell penetrating peptides (ARCPPs) across lipid bilayers involves the formation of trans-membrane hydrophilic pores. However, there are still many unanswered questions regarding the role of relevant peptide and membrane properties on translocation efficiency, such as membrane charge and acidity, peptide length and conformational flexibility, etc., as to state that there is clear consensus on how ARCPPs work under physiological conditions. In the present work, we develop a Molecular Theory (MT) to systematically investigate the binding of arginine-rich peptides to lipid bilayers bearing a cylindrical pore. The MT accounts for the acid-base equilibrium of all titratable species, the electrostatic and steric interactions as well as entropic effects, while also incorporating specific molecular information of the peptides, including size, shape, conformation, protonation state, and charge distribution. The state of protonation of lipids in the membrane is not assumed a priori but predicted locally depending on the interplay between molecular organization and the aforementioned physico chemical effects. We present a methodical investigation of the effect of pore size, peptide concentration, and chain length, on the extent of peptide adsorption and insertion into the pore. Our results suggest that membrane adsorption plays a key role on peptide translocation. For peptides shorter than ARG9, adsorption increases significantly with chain length, but saturates for longer peptides. However, such behavior only occurs at relatively low peptide concentrations as increasing peptide concentration favors adsorption of the shorter molecules. Peptide inclusion into the pore shows a non-monotonic dependence on the pore radius. We also observe that to favor peptide adsorption, the pore surface becomes more negatively charged than the rest of the membrane surface.