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Calculation of interaction energy between voltage-gated potassium channel Kv1.2 and

Molecular modeling group Bioengineering department Biology Faculty M.V.Lomonosov Moscow State University. Calculation of interaction energy between voltage-gated potassium channel Kv1.2 and blocker agitoxin Valery N. Novoseletsky Maria A. Bolshakova

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Calculation of interaction energy between voltage-gated potassium channel Kv1.2 and

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  1. Molecular modeling group Bioengineering department Biology Faculty M.V.Lomonosov Moscow State University Calculation of interaction energy between voltage-gated potassium channel Kv1.2 and blocker agitoxin Valery N. Novoseletsky Maria A. Bolshakova Konstantin V. Shaitan Moscow 2013

  2. Voltage-Dependent Potassium Channels Pore-forming membrane proteins that open or close in response to changes in the transmembrane voltage. Potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. Action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. During action potentials, voltage-dependent potassium channelsplay a crucial role in returning the depolarized cell to a resting state.

  3. Crystal Structure of a Mammalian Voltage-Dependent K+ Channel (Long, Campbell, MacKinnon, 2005)

  4. Crystal Structure of a Mammalian Voltage-Dependent K+ Channel Transmembrane domain scheme: helices S1-S4 form the voltage-sensing domain, helicesS5 and S6 take place in the ions conduction.

  5. Crystal Structure of a Mammalian Voltage-Dependent K+ Channel Side view: voltage-sensing domain, pore domain and selective filter.

  6. Scorpion venom toxin – agitoxin Agitoxin structure was determined by NMR(Kresel, Kasibhatha, 1995). Structure has highly conserved motif consisting of - 3 antiparallelβ-sheets - α-helix - 3 disulfide bridges Agitoxin specifically blocks Kv1.2 channel with high affinity (Kd < 1 nmol/L)

  7. Kv1.2 channel complex with agitoxin Extracellular and membrane view. Highly conserved residues involved in binding are marked (pdb-codes1AGT for agitoxin, 2A79 for channel).

  8. Molecular system preparation

  9. Potential of mean force with umbrella sampling 1. Pulling the toxin away fromthe channel using steered molecular dynamics Toxin-channel distance increases with time from 2.5 nm at 0 ps to 7 nm at 500 ps.

  10. Potential of mean force with umbrella sampling 2. Frame selection 3.Configuration space sampling

  11. Potential of mean force with umbrella sampling 4. PMF extraction and ΔG calculation Dependence of PMF on toxin-channel distance in 0.1 MNaCl solution.

  12. Potential of mean force with umbrella sampling 5. Error estimation 22 ± 2kcal/mol Dependence of PMF on toxin-channel distance in 0.1 MNaCl solution. Binding energy is equal to the max PMF value and consists 22 ± 2kcal/mol.

  13. Effect of ionic strength on the free energy of binding 0, 025M 25 20 15 10 5 0 0, 05M 0,1M 0,2M 0,4M E (kcal/mol) z (nm) Binding energy drops with the increase of ionic strength.

  14. Comparison of the results * Zachariae et al, 2008 ** Our data *** Khabiri et al, 2011

  15. Conclusion • Structural model of agitoxin-channel complex was constructed • Free energy binding was calculated using potential of mean force and umbrella sampling • Obtained results differ from experimental data. Probable reason is in the mistake of system preparation

  16. Thank you for attention!

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