A hierarchical molecular continuum approach to predict protein ion channel enenergetics
speaker: Maria Kurnikova (Carnegie Mellon University)abstract: Ion channels in cell membranes play important roles in cell physiology. Such channels are formed by integral membrane proteins. Ion channels conduct ions driven by electric potential and a di erence in ionic concentrations across the membrane. Ion current through the channel can often be described using the continuum theory of drift-di usion (known as a Nernst-Plank (NP) equation) supplemented by a description of the electrostatic eld in the system via the Poisson Equation (PE) 1,2. In the absence of a current the Poisson-Nernst-Plank (PNP) theory reduces to the Poisson-Boltzmann equa- tion. To account for ion interaction with the protein forming the channel we have recently introduced a soft repulsion (SR) model 3. The model has been applied to compute current-voltage character- istics of an alpha-hemolysin channel. We have also investigated model dependency on the choice of the di usion constant distribution. The PNP-SR algorithm is implemented in a new ecient parallel Poisson, Poisson-Boltzmann, and PNP equation solver, also incorporated in a graphical molecular modeling package HARLEM. We have also developed a graphical processing unit (GPU) PE solver 4. The dependency of current-voltage characteristics of an -hemolysin channel on the channel po- sition within the membrane was also studied 5. The presence of the membrane environment also in uences protonation state of the residues at the boundary of the water-lipid interface. We predict that Asp and Lys residues at the protein rim change their protonation state upon penetration to the lipid environment. Free energies of protein insertion in the membrane for di erent penetration depths was estimated using the Poisson-Boltzmannsolvent accessible surface area (PBSASA) model. The results show that recti cation and reversal potentials are very sensitive to relative position of channel in the membrane, which, in turn, contributes to alternative protonation states of lipid penetrating ionizable groups. The prediction of channel position based on the matching of calculated recti ca- tion with experimentally determined recti cation is in good agreement with recent neutron reection experiments. Based on the results we conclude that -hemolysin membrane position is determined by a combination of several factors and not only by the pattern of the surface hydrophobicity as is typically assumed. 1. Kurnikova M.G., R.D. Coalson, P. Graf and A. Nitzan, A lattice relaxation algorithm for 3D Poisson-Nernst-Planck theory with application to ion transport through the Gramicidin A channel. Biophys. J., 76, 642-656 (1999) 2. Mamonov A., R. Coalson, A. Nitzan and M. Kurnikova, The role of the dielectric barrier in narrow biological channels: a novel composite approach to modeling single channel currents. Biophys. J., 84(6), 3646-3661 (2003) 3. Simakov N and M. Kurnikova, Soft Wall Ion Channel in Continuum Representation with Application to Modeling Ion Currents in -Hemolysin. J. Phys. Chem. B, 114(46), 15180- 15190 (2010) 4. Simakov, N.A. and Kurnikova, M.G. Graphical Processing Unit accelerated Poisson equation solver and its application for calculation of single ion potential in ion-channels. Molec. Based Math. Biol. Vol 1, pp 151-163 (2013) 5. Simakov, N.A. and Kurnikova, M.G, Membrane Position Dependency of the pKa and Con- ductivity of the Protein Ion Channel, J. Membrane Biol. https:/doi.org10.1007s00232-018-0013-3 (2018)
timetable:
Wed 3 Oct, 9:00 - 10:15, Aula Dini
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