Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking β-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial β-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.

Fipronil, which targets GABAA receptors (GABAARs), is the first phenylpyrazole insecticide widely used in crop protection and public hygiene. However, its high toxicity on fishes greatly limited its applications. In the present study, a series of computational methods including homology modeling, docking, and molecular dynamics simulation studies were integrated to explore the binding difference of fipronil with GABAARs from fruitfly and zebrafish systems. It was found that, in the zebrafish system, the H-bond between 6'Thr and fipronil exerted key effects on the recognition of fipronil, which was absent in the fruitfly system. On the other hand, in the fruitfly system, strong electrostatic interaction between 2'Ala and fipronil was favorable to the binding of fipronil but detrimental to the binding in the zebrafish system. These findings marked the binding difference of fipronil with different GABAARs, which might be helpful in designing selective insecticides against pests instead of fishes.

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The Car-Parrinello molecular dynamics (CPMD) method was used to study the dynamic characteristics of the cation-pi interaction between ammonium and benzene in gaseous and aqueous media. The results obtained from the CPMD calculation on the cation-pi complex in the gaseous state were very similar to those calculated from the Gaussian98 program with DFT and MP2 algorithms, demonstrating that CPMD is a valid approach for studying this system. Unlike the interaction in the gaseous state, our 12-ps CPMD simulation showed that the geometry of the complex in aqueous solution changes frequently in terms of the interaction angles and distances. Furthermore, the simulation revealed that the ammonium is constantly oscillating above the benzene plane in an aqueous environment and interacts with benzene mostly through three of its hydrogen atoms. In contrast, the interaction of the cation with the aromatic molecule in the gaseous state involves two hydrogen atoms. In addition, the free energy profile in aqueous solution was studied using constrained CPMD simulations, resulting in a calculated binding free energy of -5.75 kcal/mol at an optimum interaction distance of approximately 3.25 A, indicating that the cation-pi interaction between ammonium and benzene is stable even in aqueous solution. Thus, this CPMD study suggested that the cation-pi interaction between an ammonium (group) and an aromatic structure could take place even on surfaces of protein or nucleic acids in solution.