**M. Harunur Rashid, Somayeh Mahdavi and Serdar Kuyucak \***

School of Physics, University of Sydney, New South Wales 2006, Australia; harun@physics.usyd.edu.au (M.H.R.); mahdavi@physics.usyd.edu.au (S.M.)

**\*** Author to whom correspondence should be addressed; serdar@physics.usyd.edu.au; Tel.: +61-2-9036-5306; Fax: +61-2-9036-7158.

Received: 19 December 2012; in revised form: 30 January 2013; Accepted: 7 February 2013; Published: 13 March 2013

**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.

**Keywords:** conotoxins; ShK toxin; ion channels; docking; molecular dynamics; potential of mean force; free energy perturbation
