Credit: © 2008 Wiley

Proteins are naturally folded in a combination of α-helices and β-sheets formed by linear peptide strands hydrogen-bonded to each other. Misfolding, however, can lead to β-sheets aggregating, which has been linked to neurological disorders. Aminopyrazole derivatives have been identified as promising ligands for connecting to peptide strands and preventing β-sheets from misfolding, but it is difficult to determine binding motifs in solution because of the influence of other species.

Now, Markus Gerhards at the Technical University of Kaiserslautern and co-workers have investigated the intrinsic binding properties of two aminopyrazoles by examining the clusters formed between them and small peptides in the gas phase1. Characterization by mass-, isomer- and state-selective spectroscopy enabled the researchers to isolate even closely related aggregates. This in turn led to the determination of the conformation of the peptide for each cluster, as well as the number and strength of inter- and intramolecular hydrogen bonds. The results, supported by theoretical calculations, showed that each ligand–peptide combination had a clear preference for one binding motif.

In particular, for each favoured cluster the strongest hydrogen bonds to the peptide were formed by the nitrogen atoms of the pyrazole ring. Such information can help to optimize the design of ligands for the prevention of peptide aggregation.