Design, Synthesis and Conformational Analysis of Hydrogen Bond Surrogate (HBS) Stabilized Helices in Natural Sequences. Helically Constrained Peptides for Potential DNA-Binding

Abstract

Thesis titled, “Design, Synthesis and Conformational Analysis of Hydrogen Bond Surrogate (HBS) Stabilized Helices in Natural Sequences. Helically Constrained Peptides for Potential DNA-Binding”, describes the development of a novel covalent hydrogen bond surrogate (HBS) model and its incorporation in short (4-8 residues) unstructured peptide sequences with coded amino acids, through a facile solution phase synthetic method (SPSM), to constrain them into α- helical conformations with highest known stabilities and helicities. The synthetic protocol was developed for mass scale combinatorial synthesis of helical peptidomimetics. NMR, FT-IR, CD spectra and molecular dynamics simulations of variants of the HBS-constrained helical peptidomimetics were analyzed to determine the optimum number of sp2 atoms and the residue preferences that yield both the α-helical and the 310-helical folds with high structural integrity in the shortest sequences. The HBS-constrained helical peptidomimetics were used to derive experimental evidence that the 2-state Helix-Coil Transition occurs at each residue during helix folding and that this process is entropically driven. Further, the role of temperature on the denaturation of secondary structures was investigated using these HBS-constrained helical models. Helical peptidomimetics of the DNA-binding domain in the zinc-finger human TTK protein have been synthesized, which have proven to be promising mimics for DNA-binding and subsequent transcription regulation.