Molecular recognition processes play a central role in chemistry and biology. For their precise control a thorough understanding of secondary interactions is of utmost importance. Such chemical forces are weak and therefore commonly also difficult to characterize. They provide an overall conformational stabilizing effect by acting in a cooperative manner, which also offers an opportunity for their accurate characterization.<br/>We use β-hairpin peptidomimetics as model systems for studying weak interactions, such as hydrogen bonding and halogen bonding. We characterize such weak interactions in a biologically relevant context by the solution NMR investigation of the folding of strategically designed β-hairpin peptides. These cyclic β-hairpins differ only in a side chain hydroxy-to-methyl substitution (Figure 1), and hence allow the measurement of the extent a single interstrand hydrogen bond promotes β-hairpin folding. Using a combined computational and spectroscopic ensemble analysis we show that the peptide capable of forming an interstrand hydrogen bond has a higher conformational stability as compared to that lacking this interaction. Using this method we investigate halogen bonding by measuring its impact on β-hairpin folding. In addition, we have used the peptide model systems to evaluate the ability of various spectroscopic and computational methods to determine slight differences in conformational stability.<br/>The knowledge gained on the study of β-hairpin peptides was also applied to mimick α-helical inhibitors for the p53-MDM2 protein-protein interaction, which is an attractive target for cancer treatment.

Investigation of weak interactions using a β-hairpin peptide model system

253rd National Meeting (2017)

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