Computational Studies of Marine Toxins Targeting Ion Channels

Abstract

Toxins from marine animals offer novel drug leads for treatment of diseases involving ion channels. Computational methods could be very helpful in this endeavour in several ways, e.g., (i) constructing accurate models of the channel-toxin complexes using docking and molecular dynamics (MD) simulations; (ii) determining the binding free energies of toxins from umbrella sampling MD simulations; (iii) predicting the effect of mutations from free energy MD simulations. Using these methods, one can design new analogs of toxins with improved affinity and selectivity properties. Here we present a review of the computational methods and discuss their applications to marine toxins targeting potassium and sodium channels. Detailed examples from the potassium channel toxins—ShK from sea anemone and κ-conotoxin PVIIA—are provided to demonstrate capabilities of the computational methods to give accurate descriptions of the channel-toxin complexes and the energetics of their binding. An example is also given from sodium channel toxins (µ-conotoxin GIIIA) to illustrate the differences between the toxin binding modes in potassium and sodium channels.

Computational Approaches for Designing Potent and Selective Analogs of Peptide Toxins as Novel Therapeutics

“…This provided an important test case for the viability of the method because the structure of the complex was known [34], and there was no uncertainty in that regard. Since then, the PMF method has been used in several computational studies of toxin binding to ion channels (see [11,12] for reviews). Provided that a validated complex structure was employed and the PMF was calculated properly, the standard binding free energy was obtained accurately in all cases.…”

“…This has been taken up in a recent computational study of the Na V 1.4–μ-GIIIA system [12], where good agreement with the available mutation data and the binding free energy has been obtained. The proposed binding mode provides a complete blocking of the pore as observed experimentally (Figure 5).…”

“…Most of the computational work on toxin binding to ion channels has been done on potassium channels [11,12], because their crystal structures have been available since 1998 [62]. Here we will focus on Kv1 channels, and in particular Kv1.3, which is an established target for the treatment of autoimmune diseases.…”

“…Unfortunately, there are limited functional data on binding of μ-PIIIA [82,83], so it is difficult to check the validity of the complex structure and the Na V 1.4 model used in [81]. The possibility of multiple binding modes with similar binding free energies needs to be investigated further using the Na V 1.4 model that has already been validated with the μ-GIIIA data [12]. In two other computational studies, the binding of tetrodotoxin to Na V 1.4 has been investigated [84,85], where completely different binding modes were predicted.…”

“…First, one can construct accurate models of the receptor–ligand complexes using docking methods and molecular dynamics (MD) simulations [10–12]. Binding modes obtained from such models provide valuable hints for identifying suitable mutations that could achieve the desired selectivity.…”