Amol S. Kotmale

A Synthetic Zipper Peptide Motif Orchestrated via Co-operative Interplay of Hydrogen Bonding, Aromatic Stacking, and Backbone Chirality

Here, we report on a new class of synthetic zipper peptide which assumes its three-dimensional zipper-like structure via a co-operative interplay of hydrogen bonding, aromatic stacking, and backbone chirality. Structural studies carried out in both solid- and solution-state confirmed the zipper-like structural architecture assumed by the synthetic peptide which makes use of unusually remote inter-residual hydrogen-bonding and aromatic stacking interactions to attain its shape. The effect of chirality modulation and the extent of noncovalent forces in the structure stabilization have also been comprehensively explored via single-crystal X-ray diffraction and solution-state NMR studies. The results highlight the utility of noncovalent forces in engineering complex synthetic molecules with intriguing structural architectures.

Carboxamide versus Sulfonamide in Peptide Backbone Folding: A Case Study with a Hetero Foldamer

Strikingly dissimilar hydrogen-bonding patterns have been observed for two sets of closely similar hetero foldamers containing carboxamide and sulfonamides at regular intervals. Although both foldamers maintain conformational ordering, the hydrogen-bonding pattern and backbone helical handedness differ diametrically.

The role of N-terminal proline in stabilizing the Ant–Pro zipper motif

Hetero-chiral hybrid peptides of the general sequence LαβnDαβn featuring proline (Pro, a constrained α-amino acid) and anthranilic acid (Ant, a constrained β-amino acid) as building blocks, where n = 2, 4 etc., form a three-dimensional zipper-like architecture. These zipper peptides attain stable conformation by balancing the co-operative contribution of two competing non-covalent forces, namely hydrogen bonding and aromatic stacking. However, the selection of the N-terminal residue also stands to be one of the key contributors in stabilising the unusually long-range intramolecular hydrogen bond, featuring 26 atoms in the H-bonded ring observed at the termini. This article deals with the substitution alterations at the N-terminus of the zipper motif and their consequent influences on its structure and stability. In this study, the N-terminal Pro residue of the zipper motif was substituted with a flexible amino acid, alanine, and a constrained acyclic amino acid, 2-aminoisobutyric acid, to investigate the role of N-terminal proline in stabilizing the Ant–Pro zipper motif, and its stabilities were assessed by employing solution-state NMR and restrained MD simulation studies.

Bile acid hydrazides: gelation, structural, physical and spectroscopic properties

Synthesis and gelation properties of a series of novel bile acid hydrazides are presented. These compounds are found to undergo self-assembly leading to organogelation in certain organic solvents. Compound 1 was found to be the most “effective” gelator in this series. The properties of this gel have been thoroughly investigated by conventional methods typical for molecular gel studies. Sol–gel transition temperature (Tg) of chloroform gels of compounds 1 and 3 was found to increase with increase in the chain length. Sol–gel transition was probed using the isothermal time test and results show that there is instantaneous increase in both the moduli after shear melting, which suggests that the kinetics of formation of the network was very fast. IR and NMR studies revealed hydrogen bonding between amidic carbonyl in the side chain and hydroxyl groups of cholic acid.

Coumarin-Appended Stable Fluorescent Self-Complementary Quadruple-Hydrogen-Bonded Molecular Duplexes

In this paper we report a coumarin-conjugated self-assembling system adorned with valuable features such as high duplex stability and a built-in fluorophore, which would augment its application potential. This system forms a highly stable molecular duplex in a nonpolar solvent (Kdim > 1.9 × 107 M-1 in CDCl3). Due to the fluorescent property of coumarin, these new structural motifs may find potential application in material chemistry and supramolecular chemistry.

Acyclic αγα-Tripeptides with Fluorinated- and Nonfluorinated-Furanoid Sugar Framework: Importance of Fluoro Substituent in Reverse-Turn Induced Self-Assembly and Transmembrane Ion-Transport Activity

Acyclic αγα-tripeptides derived from fluorinated-furanoid sugar amino acid frameworks act as reverse-turn inducers with a U-shaped conformation, whereas the corresponding nonfluorinated αγα-tripeptides show random peptide conformations. The NMR studies showed the presence of bifurcated weak intramolecular hydrogen bonding (F···HN) and N+···Fδ- charge-dipole attraction compel the amide carbonyl groups to orient antiperiplanar to the C-F bond, thus, demonstrating the role of the fluorine substituent in stabilizing the U-shaped conformation. The NOESY data indicate that the U-shaped tripeptides self-assembly formation is stabilized by the intermolecular hydrogen bonding between C═O···HN with antiparallel orientation. This fact is supported by ESI-MS data, which showed mass peaks up to the pentameric self-assembly, even in the gas phase. The morphological analysis by FE-SEM, on solid samples, showed arrangement of fibers into nanorods. The antiparallel self-assembled pore of the fluorinated tripeptides illustrates the selective ion-transport activity. The experimental findings were supported by DFT studies.

Triazine-Based Highly Stable AADD-Type Self-Complementary Quadruple Hydrogen-Bonded Systems Devoid of Prototropy

A new class of 1,3,5-triazine-based quadruple hydrogen-bonded system featuring AADD-type self-complementary arrays has been developed and characterized. This system forms highly stable molecular duplex in non-polar solvent (Kdim >1.9×107  m-1 in CDCl3 ) without prototropy-related issues, raising its prospects for application in supramolecular polymer science.

Self-Assembly of Fluorinated Sugar Amino Acid Derived α,γ-Cyclic Peptides into Transmembrane Anion Transport

Syntheses of fluorinated sugar amino acid derived α,γ-cyclic tetra- and hexapeptides are reported. The IR, NMR, ESI-MS, CD, and molecular modeling studies of cyclic tetra- and hexapeptides showed C2 and C3 symmetric flat oval- and triangular-ring shaped β-strand conformations, respectively, which appear to self-assemble into nanotubes. The α,γ-cyclic hexapeptide (EC50 = 2.14 μM) is found to be a more efficient ion transporter than α,γ-cyclic tetrapeptide (EC50 = 14.75 μM). The anion selectivity and recognition of α,γ-cyclic hexapeptide with NO3- ion is investigated.

3-Aminothiophenecarboxylic acid (3-Atc)-induced folding in peptides

This paper describes the consequences of incorporating a constrained heterocyclic aromatic β-amino acid 3-aminothiophenecarboxylic acid (3-Atc) into peptides containing β-turn forming elements such as Pro-Gly motif and the effect on the secondary structural architecture of the entire peptide backbone. Conformational investigations of oligomers comprising an α,β,α peptide sequence were carried out by single-crystal X-ray diffraction, solution-state NMR, nOe-restrained MD simulation and circular dichroism studies. The results suggested that these peptide sequences assume helical architecture. The helical folding in the oligomers was found to be devoid of inter-residual H-bonding, instead found to be stabilized by a co-operative effect of 6-membered H-bonding within the 3-Atc unit and conformational restrictions of individual amino acids in the peptide backbone.

Conformational studies of Ant–Pro motif-incorporated cyclic peptides: gramicidin S and avellanin

This paper reports conformational changes observed in cyclic bioactive peptides such as gramicidin S and avellanin upon incorporation of a pseudo-β (C9) Ant–DPro turn motif in their structural frameworks. Solution-state studies suggested that a synthetic gramicidin S analog exhibits a β-sheet conformation with C9 and C17 intramolecular hydrogen bonding patterns, while its truncated analog disturbs the β-sheet conformation. Structural details were obtained using a combination of CD studies, X-ray crystal structure studies and nOe-based MD simulation studies.