The molecular torsion balance concept was applied to a new conformationally controlled scaffold and synthesized to accurately evaluate pair-wise amino acid interactions in an anti-parallel β-sheet motif. The design exploits restricted rotation around an aryl-nitrogen bond to impose a two-state folding manifold. The combination of (<i>ortho</i>-tolyl)amide and biphenyl structural units gives a geometry that emulates a β-turn. The aim of this study was to improve the alignment between the amino acid sequences attached to the upper and lower aromatic rings to promote hydrogen bonding. Bromo substituents were introduced <i>ortho</i> to the upper side chains and compared to a control to test our hypothesis. 2D ROESY data clearly indicated a perturbation in the orientation of the upper side chains for the dibromo scaffold. 1H and 2D ROESY NMR analyses reveal bromine addition has improved the balance’s shape to mimic the ends of an anti-parallel β-sheet. The side chains participating in hydrogen bond formation have the correct configuration and required distance in hydrogen bonded amino acids. Furthermore, we have identified the NH amide proton of the upper side chain to be the hydrogen bond donor and the glycine acetamide of the lower side chain as the hydrogen bond acceptor.

Synthesis and NMR analysis of a conformationally controlled β-turn mimetic torsion balance

252nd National Meeting (2016)

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