Julia Setzler

Differential hERG ion channel activity of ultrasmall gold nanoparticles

Understanding the mechanism of toxicity of nanomaterials remains a challenge with respect to both mechanisms involved and product regulation. Here we show toxicity of ultrasmall gold nanoparticles (AuNPs). Depending on the ligand chemistry, 1.4-nm-diameter AuNPs failed electrophysiology-based safety testing using human embryonic kidney cell line 293 cells expressing human ether-á-go-go-Related gene (hERG), a Food and Drug Administration-established drug safety test. In patch-clamp experiments, phosphine-stabilized AuNPs irreversibly blocked hERG channels, whereas thiol-stabilized AuNPs of similar size had no effect in vitro, and neither particle blocked the channel in vivo. We conclude that safety regulations may need to be reevaluated and adapted to reflect the fact that the binding modality of surface functional groups becomes a relevant parameter for the design of nanoscale bioactive compounds.

SLIM: An improved generalized Born implicit membrane model

In most implicit continuum models, membranes are represented as heterogeneous dielectric environments, but their treatment within computationally efficient generalized Born (GB) models is challenging. Despite several previous attempts, an adequate description of multiple dielectric regions in implicit GB‐based membrane models that reproduce the qualitative and quantitative features of Poisson–Boltzmann (PB) electrostatics remains an unmet prerequisite of qualitatively correct implicit membrane models. A novel scheme (SLIM) to decompose one environment consisting of multiple dielectric regions into a sum of multiple environments consisting only of two dielectric regions each is proposed to solve this issue. These simpler environments can be treated with established GB methods. This approach captures qualitative features of PB electrostatic that are not present in previous models. Simulations of three membrane proteins demonstrate that this model correctly reproduces known properties of these proteins in agreement with experimental or other computational studies.

Joint Experimental and Theoretical Investigation of the Interaction Between Antimicrobial Peptides, Gold Nanoparticles and Membranes

Antimicrobial peptides and gold nanoparticles (AuNPs) are interesting novel classes of pharmaceutically active compounds. To understand and optimize their efficacy, interactions of these systems with biological membranes need to be characterized. Given the wide range of synthetic possibilities, either by sequence design (peptides) or size, composition and ligand shell (nanoparticles), computational methods may help designing active compounds with predictable membrane permeability. Here we investigate a range of implicit membrane models, as extensions of our implicit solvent force field PFF02, to understand details of experimentally observed membrane association properties of naturally occurring antimicrobial peptides, in particular Gramicidin A/S and ligand stabilized gold nanoparticles of different size. Membrane association and penetration were studied in black lipid membrane (BLM) experiments using DOPC or DiphPC/DiphPG and DiphPE, model membranes. For Gram A we observed the transient formation of individual pores in the experiments, which are rationalized by simulations showing the dimerization of the helical peptides in the membrane. For Gram S, in agreement with the modeling results, we observe only small, fluctuating currents. We also observe size selective membrane association of the gold nanoparticles, where membrane integration of nanoparticles of 15 nm diameter generated ion-selective currents, while smaller 1.4 nm particles did not show such effects.