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Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session VI Abstracts
Computational Design of Drugs for Autoimmune Diseases from Peptide Toxins
Serdar Kuyucak
.
University of Sydney, Sydney, NSW, Northwest Territorie, Australia.
Developing drugs from natural products such as toxins has a great potential but progress has
been slow due to complexity of the problem. Combination of experimental methods with
accurate simulations of protein-peptide complexes could help to improve this situation. Two
main computational challenges are construction of accurate models of complexes and prediction
of reliable binding free energies. The former can be achieved using docking programs, followed
by refinement via molecular dynamics (MD) simulations. Binding free energies can be obtained
from the potential of mean force (PMF) calculations. We showed the feasibility of this approach
in a potassium channel-charybdotoxin complex, where the complex structure is known from
NMR [1]. As a real-life application, we considered ShK toxin, which binds to Kv1.3 channels
with very high affinity, and therefore, it is developed as an immunosuppressant drug. However, it
also binds to Kv1.1 with similar affinity, and it essential to find analogues of ShK with increased
selectivity for Kv1.3. We have developed accurate models for Kv1.1-1.3 channels in complex
with ShK, which are validated by comparing with available mutagenesis data and binding free
energies [2]. The complex structures of ShK indicated several mutations on ShK (e.g. K18A,
R29A) that could enhance its Kv1.3/Kv1.1 selectivity. Free energy perturbation and PMF
calculations of the K18A mutation on ShK yielded about 2 kcal/mol improvement on its
Kv1.3/Kv1.1 selectivity, which has been confirmed in subsequent experiments [3]. The
computational methods considered here would be very useful in rational drug design, especially
in solving selectivity problems for unintended targets.
[1] P.C. Chen and S. Kuyucak. 2011. Biophys. J. 100:2466-2474.
[2] M.H. Rashid and S. Kuyucak. 2012. J. Phys. Chem. B 116:4812-4822.
[3] M.H. Rashid et al. 2013. PloS ONE 8:e78712.
