Synthesis, Structure and Mechanical properties of Peptide Mimetics

Shit, Ananda (2025) Synthesis, Structure and Mechanical properties of Peptide Mimetics. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

This thesis is entitled “Synthesis, structure, and mechanical properties of peptide mimetics.” It is all about the design, synthesis, characterization, conformational analysis, self-assembly, and application of peptidomimetics. This thesis mainly focuses on the development of synthetic peptidomimetics which are composed of both genetically coded and non-coded amino acids for studying and understanding the molecular self-assembly processes of these peptides in supramolecular helices, sheets, and to study their further aggregation behavior in forming gels or nanomaterials like tube, vesicle, fiber, porous structure and their versatile applications in several fields. This thesis discusses the structural behavior of peptide-stabilized nanoparticles, which are being used extensively in the fabrication of magnetic paper-based origami, which has diverse applications in the field of actuation and soft robotics. The development of α, ε-hybrid peptide-stabilized magnetic nanoparticles and their application to fabricate a paper-based actuator has been reported. From single-crystal diffraction analysis, the nitropeptide 2 has an extended structure with a trans geometry. The one-pot in situ multiple oxidation-reduction reaction of a synthetic nitropeptide solution in ammonium hydroxide and FeCl₂ results in the formation of Fe₃O₄ nanoparticles. The reduction reaction replaces the nitro group with an amine group, which finally acts as capping agent for the stabilization of the Fe₃O₄ nanoparticles. Paper-based soft magneto machines with multivariant actuation modes such as contraction−expansion, bending, and uplifting locomotion have been studied. The device has potential as controllable paper-based soft robots. The thesis also represents structure and mechanical property of novel designer peptidomimetics containing ferrocene a molecular scaffold, and with that moiety different aliphatic amino acids have been introduced. This research reports the development of a novel switchable helix from ferrocene-hinged peptide mimetics synthesized using 1,1ʹ-ferrocene dicarboxylic acid and chiral amino acids leucine, valine and an achiral amino acid ⍺-amino isobutyric acid (Aib). The peptide mimetic exhibits robust structure, spherical aggregate morphology, and exceptional stimuli responsiveness. 1,1ʹ-Disubstituted ferrocene scaffolds can guide the folding of short peptides. These scaffolds carry hydrogen-bonding groups. They help form turns and helix-like shapes. The two cyclopentadienyl rings in ferrocene are about ~3.3 Å apart. This matches the typical distance between hydrogen bond donor and acceptor groups in β-sheets. As a result, peptides attached to the ferrocene stay close enough to interact. This promotes intramolecular hydrogen bonding. Such bonding supports the formation of stable 3D structures. The structure is stabilized by multiple intramolecular hydrogen bonds. The ferrocene hinged peptide mimetic shows a structural switch in response to external stimuli like solvent polarity and temperature. Like an ideal hinge, such as gates and tweezers, this molecular device reproduced the mechanism, while remaining soluble and responsive to stimuli. This work paves the way for advancements in mechano-chemical molecules for innovative technologies in environmental monitoring and electronics. This thesis also includes the structure and function of ester bio isosteres molecules which are getting introduced with a chain of noncoded amino acids which are selectively chosen for a particular purpose. This novel peptide mimetic is designed for selective folding and conformation. The peptide mimetic comprises β-alanine, L-leucine, α-amino isobutyric acid, m-nitro cinnamic acid synthesized via solution-phase coupling methods. In its solid state, the molecule adopts a hairpin conformation with two perpendicular naphthalene rings. A β-hairpin conformation and extended β-pleated parallel sheet assembly have been characterized by single crystal x-ray diffraction analysis. The centrally located BINOL segment act as bioisotare and nucleates a chain reversal in β-turn conformation. Two intramolecular cross-strand hydrogen bonds stabilize the peptide fold. Intermolecular NH…. O=C hydrogen bonds connect the hairpins into an infinitely extended β-sheet. The structure is also stabilized by face to edge π-stacking interactions. This peptide mimetic represents a promising tool for foldamer design, with potential applications in molecular devices. This thesis also talks about mechanochemistry, which offers exciting opportunities for molecular-level engineering of stress-responsive properties of compounds. Reactive sites, sometimes called mechanophores, have been reported to increase the material toughness, to make the material mechanochromic or optically healable. This study introduces a novel approach for stimuli responsive molecular machine, facilitated by multimodal mechanophores. The key innovation lies in the use of a robust molecule, derived from a 1,1’-ferrocene dicarboxylic acid, 3-amino n-propanol, and phthalic anhydride or naphthalic anhydride which acts as a stained molecule to undergo stimuli responsive open and close action. This unique design enables the molecule to proceed efficiently by changing solvent polarity. In polar protic solvent, the molecule adopt close structure, exhibits axial chirality and CD active. In polar aprotic solvent, the molecule adopts open structure, no axial chirality and CD inactive. Thus, the synthesis and mechanical properties of a multimodal mechanophores based on ferrocene embedded peptide mimetics have been explored.

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