This study employs molecular dynamics (MD) simulations to investigate the adsorption and aggregation behavior of simple polyarginine cell-penetrating peptides (CPPs), specifically modeled as R9 peptides, at zwitterionic phosphocholine POPC membranes under varying ionic strengths of two peptide concentrations and two concentrations of NaCl and CaCl2. The results reveal an intriguing phenomenon of R9 aggregation at the membrane, which is dependent on the ionic strength, indicating a salting-out effect. As the peptide concentration and ionic strength increase, peptide aggregation also increases, with aggregate lifetimes and sizes showing a corresponding rise, accompanied by the total decrease of adsorbed peptides at the membrane surface. Notably, in high ionic strength environments, large R9 aggregates, such as octamers, are also observed occasionally. The salting-out, typically uncommon for short positively charged peptides, is attributed to the unique properties of arginine amino acid, specifically by its side chain containing amphiphilic guanidinium (Gdm+) ion which makes both intermolecular hydrophobic like-charge Gdm+ - Gdm+ and salt-bridge Gdm+ - C-terminus interactions, where the former are increased with the ionic strength, and the latter decreased due to electrostatic screening. The aggregation behavior of R9 peptides at membranes can also be linked to their CPP translocation properties, suggesting that aggregation may aid in translocation across cellular membranes.

• Klíčová slova
• Ionic strength, Molecular dynamics simulations, Peptide aggregation, Phosphocholine lipid bilayers, Polyarginines, Salting-out,
• Publikační typ
• časopisecké články MeSH

Models of the hydrogenoxalate (bioxalate, charge -1) and oxalate (charge -2) anions were developed for classical molecular dynamics (CMD) simulations and parametrized against ab initio molecular dynamics (AIMD) data from our previous study (Kroutil et al. (2016) J Mol Model 22:210). The interactions of the anions with water were described using charges scaled according to the electronic continuum correction approach with rescaling of nonbonded parameters (ECCR), and those descriptions of anion interactions were found to agree well with relevant AIMD and experimental results. The models with full RESP charges showed excessively strong electrostatic interactions between the solute and water molecules, leading to an overstructured solvation shell around the anions and thus to a diffusion coefficient that was much too low. The effect of charge scaling was more evident for the oxalate dianion than for the hydrogenoxalate anion. Our work provides CMD models for ions of oxalic acid and extends previous studies that showed the importance of ECCR for modeling divalent ions and ions of organic compounds. Graphical abstract The radial distribution function between a water oxygen (Ow) and an oxygen of the oxalate dianion (Ox) significantly improved when scaled charges were applied to the anion.

• Klíčová slova
• AIMD, Ab initio molecular dynamics, CMD, Classical molecular dynamics, ECCR, Electronic continuum correction, Hydrogenoxalate, Oxalate, Oxalic acid anions,
• Publikační typ
• časopisecké články MeSH