Adsorption of Synthetic Cationic Polymers on Model Phospholipid Membranes: Insight from Atomic-Scale Molecular Dynamics Simulations

Abstract

Although synthetic cationic polymers represent a promising class of effective antibacterial agents, the molecular mechanisms behind their antimicrobial activity remain poorly understood. To this end, we employ atomic-scale molecular dynamics simulations to explore adsorption of several linear cationic polymers of different chemical structure and protonation (polyallylamine (PAA), polyethylenimine (PEI), polyvinylamine (PVA), and poly-l-lysine (PLL)) on model bacterial membranes (4:1 mixture of zwitterionic phosphatidylethanolamine (PE) and anionic phosphatidylglycerol (PG) lipids). Overall, our findings show that binding of polycations to the anionic membrane surface effectively neutralizes its charge, leading to the reorientation of water molecules close to the lipid/water interface and to the partial release of counterions to the water phase. In certain cases, one has even an overcharging of the membrane, which was shown to be a cooperative effect of polymer charges and lipid counterions. Protonated amine groups of polycations are found to interact preferably with head groups of anionic lipids, giving rise to formation of hydrogen bonds and to a noticeable lateral immobilization of the lipids. While all the above findings are mostly defined by the overall charge of a polymer, we found that the polymer architecture also matters. In particular, PVA and PEI are able to accumulate anionic PG lipids on the membrane surface, leading to lipid segregation. In turn, PLL whose charge twice exceeds charges of PVA/PEI does not induce such lipid segregation due to its considerably less compact architecture and relatively long side chains. We also show that partitioning of a polycation into the lipid/water interface is an interplay between its protonation level (the overall charge) and hydrophobicity of the backbone. Therefore, a possible strategy in creating highly efficient antimicrobial polymeric agents could be in tuning these polycation's properties through proper combination of protonated and hydrophobic blocks.

Counting charges on membrane-bound peptides

“…Moreover, we observe a nearly 10% larger decrease in the SHG E -field in the case of Arg 8 than Lys 8 , suggesting that the adsorption of Lys 8 results in a smaller change in interfacial potential than Arg 8 . This observation is in line with previous experimental 21 and theoretical 85 studies of these systems, which indicate that the interfacial potential ( i.e. , surface charge) does indeed decrease (becoming more positive) upon exposure to lysine and arginine oligomers.…”

“…The average number of bound octamers for Arg 8 and Lys 8 are 13.3 ± 1.6 and 8.4 ± 1.1 for the DMPC bilayer, respectively, while they are 22.6 ± 0.1 and 11.9 ± 3.0 for the 9 : 1 DMPC/DMPG bilayer, respectively. While each Lys 8 peptide is most likely to bind with the bilayer through one or two sidechains with the bilayer, which is qualitatively similar to observations from previous atomistic MD simulations, 85 Arg 8 is most likely to attach to the bilayer via 3–5 binding sidechains ( Fig. 5 ).…”

Martini coarse‐grained model for polyethylenimine

“…DNA aggregation by PEI was studied with and without lipid modifications on the PEI. Antimicrobial properties of PEI were studied using MD simulations of PEI and lipid bilayers . While providing molecular details on the interaction and functionality of the PEI during gene delivery, the AA, MD simulations are incapable of matching the length and time scales in the real delivery process, where the complexes formed by PEI and genetic material are ~100 nm and larger in size and the entire delivery can take hours …”

“…Antimicrobial properties of PEI were studied using MD simulations of PEI and lipid bilayers. [44,45] While providing molecular details on the interaction and functionality of the PEI during gene delivery, the AA, MD simulations are incapable of matching the length and time scales in the real delivery process, where the complexes formed by PEI and genetic material are~100 nm and larger in size and the entire delivery can take hours. [34] On a completely different scale, Yang and May [46] used the continuum level Poisson-Boltzmann theory for linear polycations to study the proton sponge effect, a mechanism hypothesized for PEI-mediated gene delivery.…”

Molecular Mechanism of Polycation-Induced Pore Formation in Biomembranes

“…17 However, modeling the complete sequence of events in polycation−bilayer systems, namely, adsorption from solution on the bilayer, followed by insertion into the bilayer interior and eventual pore formation, is currently beyond the time scales accessible through equilibrium atomistic MD simulations. 18 Although the initial steps, i.e., polymer adsorption and insertion, have been simulated with equilibrium MD, 14,16 special enhanced sampling techniques such as the umbrella sampling method are required to model pore formation in the presence of polycations. In umbrella sampling, a biasing potential applied along a chosen reaction coordinate drives the system from one thermodynamic state to another (such as from a no-pore state to an open-pore state).…”