Rings In Main Chain Research Articles

Flexibility and Cell Permeability of Cyclic Ras-Inhibitor Peptides Revealed by the Coupled Nosé-Hoover Equation.

Quantifying the cell permeability of cyclic peptides is crucial for their rational drug design. However, the reasons remain unclear why a minor chemical modification, such as the difference between Ras inhibitors cyclorasin 9A5 and 9A54, can substantially change a peptide's permeability. To address this question, we performed enhanced sampling simulations of these two 11-mer peptides using the coupled Nosé-Hoover equation (cNH) we recently developed. The present cNH simulations realized temperature fluctuations over a wide range (240-600 K) in a dynamic manner, allowing structural samplings that were well validated by nuclear Overhauser effect measurements. The derived structural ensembles were comprehensively analyzed by all-atom structural clustering, mapping the derived clusters onto principal components (PCs) that characterize the cyclic structure, and calculating cluster-dependent geometric and chemical properties. The planar-open conformation was dominant in aqueous solvent, owing to inclusion of the Trp side chain in the main-chain ring, while the compact-closed conformation, which favors cell permeation due to its compactness and high polarity, was also accessible. Conformation-dependent cell permeability was observed in one of the derived PCs, demonstrating that decreased cell permeability in 9A54 is due to the high free energy barrier separating the two conformations. The origin of the change in free energy surface was determined to be loss of flexibility in the modified residues 2-3, resulting from the increased bulkiness of their side chains. The derived molecular mechanism of cell permeability highlights the significance of complete structural dynamics surveys for accelerating drug development with cyclic peptides.

Synthesis, characterization and properties of polyimides derived from a symmetrical diamine containing bis-benzimidazole rings

A new aromatic heterocyclic diamine monomer containing bis-benzimidazole rings, 2,2′-p-phenylene-bis(5-aminobenzimidazole) (PBABI), was synthesized from 2,2′-p-phenylene-bis (5-nitrobenzimidazole) with high yield via the reaction between 4-nitro-1,2-phenylenediamine and terephthalyl chloride. The composition and structure of the resulting diamine monomer were studied by means of FTIR, 1H and 13C NMR and elemental analysis. A series of polyimides holding bis-benzimidazole rings in main chain were produced by reacting PBABI with the aromatic dianhydrides 3,3′,4,4′-biphenyl tetracarboxylic dianhydride, 4,4′-oxydiphthalic anhydride, benzophenone tetracarboxylic dianhydride and pyromellitic dianhydride via a conventional, two-step procedure. X-ray diffraction and differential scanning calorimetry were employed to investigate the polyimides, revealing them essentially amorphous. The polyimides possess thermal stabilities of up to 560 °C for a 5% weight loss and glass transition temperatures above 450 °C. In addition, these high performance polymers have excellent mechanical properties, exhibiting tensile strengths of 120–180 MPa and tensile moduli of 4.83–5.79 GPa without any stretching. The rigid-rod structure of polyimides and the hydrogen bonding of their inter-macromolecular chains are most likely responsible for the outstanding properties of the polyimides.