Conformational dynamics in peptide toxins: Implications for receptor interactions and molecular design

Peptide toxins are potent and often exquisitely selective probes of the structure and function of ion channels and receptors, and are therefore of significant interest to the pharmaceutical and biotech industries as both pharmacological tools and therapeutic leads. The three-dimensional structures of peptide toxins are essential as a basis for understanding their structure-activity relationships and their binding to target receptors, as well as in guiding the design of analogues with modified potency and/or selectivity for key targets. NMR spectroscopy has played a key role in elucidating the structures of peptide toxins and probing their structure-function relationships. In this article, we highlight the additional important contribution of NMR to characterising the dynamics of peptide toxins. We also compare the information available from NMR measurements with that afforded by molecular dynamics simulations. We describe several examples of the importance of dynamics measurements over a range of timescales for understanding the structure-function relationships of peptide toxins and their receptor engagement. Peptide toxins that inhibit the voltage-gated potassium channel KV1.3 with pM affinities display different degrees of conformational flexibility, even though they contain multiple disulfide bonds, and this flexibility can affect the relative orientation of residues that have been shown to be critical for channel binding. Information on the dynamic properties of peptide toxins is important in the design of analogues or mimetics where receptor-bound structures are not available. [Display omitted] •Disulfide-rich peptide toxins can exhibit significant conformational flexibility.•While disulfide bonds confer overall structural stability, they can also be a source of conformational exchange.•Nuclear magnetic resonance spectroscopy is a valuable tool for probing dynamics over a broad range of timescales.•Dynamics can influence structure-function relationships of peptide toxins and their binding to receptors.•Dynamics should also be considered when designing analogues or mimetics of peptide toxins.