Halogen and hydrogen bonding-driven self-assembly of supramolecular macrocycles and double helices from hydrogen-bonded arylamide foldamers

Halogen bonding has been used to hold hydrogen bonded short aromatic amide foldamers to form 2 + 2 or 1 + 1 macrocycles.

Helix handedness inversion in arylamide foldamers: elucidation and free energy profile of a hopping mechanism

The free energy landscape and conformations of minima and intermediates along the stepwise handedness inversion pathway, proceeding through the simultaneous unfolding/folding of adjacent monomer–monomer linkages, for a helical arylamide foldamer.

Helical arylamide foldamers: structure prediction by molecular dynamics simulations

Snapshots from molecular dynamics simulations showcase how substituent positions and linkage types affect the secondary structure properties of fluorobenzene based helical arylamides.

Mechanistic and dynamic insights into ligand encapsulation by helical arylamide foldamers

A hydrazine molecule encapsulated in an arylamide helical foldamer escaping from the “top” (top) and “side” (bottom) of the capsule in the aqueous and methanol solution, respectively.

An ab-initio study of pyrrole and imidazole arylamides

Arylamide foldamers have been shown to have a number of biological and medicinal applications. For example, a class of pyrrole-imidazole polyamide foldamers is capable of binding specific DNA sequences and preventing development of various gene disorders, most importantly cancer. Molecular dynamics (MD) simulations can provide crucial details in understanding the atomic level events related to foldamer/DNA binding. An important first step in the accurate simulation of these foldamer/DNA systems is the reparametrization of force field parameters for torsion around the aryl-amide bonds. Here we highlight our Density Functional Theory (DFT) potential energy profiles and derived force field parameters for four aryl-amide bond types for the pyrrole and imidazole building blocks extensively used in foldamer design for the DNA-binding polyamides. These results contribute to developing of computational tools for an appropriate molecular modeling of pyrrole-imidazole polyamide/DNA binding, and provide an insight into the chemical factors that influence the flexibility of the pyrrole-imidazole polyamides, and their binding to DNA.

Antibacterial Mechanism of Action of Arylamide Foldamers

ABSTRACTSmall arylamide foldamers designed to mimic the amphiphilic nature of antimicrobial peptides (AMPs) have shown potent bactericidal activity against both Gram-negative and Gram-positive strains without many of the drawbacks of natural AMPs. These foldamers were shown to cause large changes in the permeability of the outer membrane ofEscherichia coli. They cause more limited permeabilization of the inner membrane which reaches critical levels corresponding with the time required to bring about bacterial cell death. Transcriptional profiling ofE. colitreated with sublethal concentrations of the arylamides showed induction of genes related to membrane and oxidative stresses, with some overlap with the effects observed for polymyxin B. Protein secretion into the periplasm and the outer membrane is also compromised, possibly contributing to the lethality of the arylamide compounds. The induction of membrane stress response regulons such asrcscoupled with morphological changes at the membrane observed by electron microscopy suggests that the activity of the arylamides at the membrane represents a significant contribution to their mechanism of action.

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers

The emergence of drug-resistant bacteria has compromised the use of many conventional antibiotics, leading to heightened interest in a variety of antimicrobial peptides. Although these peptides have attractive potential as antibiotics, their size, stability, tissue distribution, and toxicity have hampered attempts to harness these capabilities. To address such issues, we have developed small (molecular mass <1,000 Da) arylamide foldamers that mimic antimicrobial peptides. Hydrogen-bonded restraints in the arylamide template rigidify the conformation via hydrogen bond formation and increase activity toward Staphylococcus aureus and Escherichia coli. The designed foldamers are highly active against S. aureus in an animal model. These results demonstrate the application of foldamer templates as therapeutics.