A size-modified poisson–boltzmann ion channel model in a solvent of multiple ionic species: Application to voltage-dependent anion channel

We present a new size-modified Poisson–Boltzmann ion channel (SMPBIC) model and use it to calculate the electrostatic potential, ionic concentrations, and electrostatic solvation free energy for a voltage-dependent anion channel (VDAC) on a biological membrane in a solution mixture of multiple ionic species. In particular, the new SMPBIC model adopts a membrane surface charge density and a natural Neumann boundary condition to reflect the charge effect of the membrane on the electrostatics of VDAC. To avoid the singularity difficulties caused by the atomic charges of VDAC, the new SMPBIC model is split into three submodels such that the solution of one of the submodels is obtained analytically and contains all the singularity points of the SMPBIC model. The other two submodels are then solved numerically much more efficiently than the original SMPBIC model. As an application of this SMPBIC submodel partitioning scheme, we derive a new formula for computing the electrostatic solvation free energy. Numerical results for a human VDAC isoform 1 (hVDAC1) in three different salt solutions, each with up to five different ionic species, confirm the significant effects of membrane surface charges on both the electrostatics and ionic concentrations. The results also show that the new SMPBIC model can describe well the anion selectivity property of hVDAC1, and that the new electrostatic solvation free energy formula can significantly improve the accuracy of the currently used formula. © 2019 Wiley Periodicals, Inc.     

Structure-based modeling of turnover of Bcl-2 family proteins bound to voltage-dependent anion channel 2 (VDAC2): Implications for the mechanisms of proapoptotic activation of Bak and Bax in vivo

Mitochondrial Outer Membrane (MOM) Permeabilization (MOMP) is a critical event in the mitochondrial types of apoptosis. MOMP is controled by the proteins of the Bcl-2 family and its two proapoptotic members Bak and Bax are the key effectors of MOMP. Voltage-dependent anion channel 2 (VDAC2) is an integral membrane protein that plays an important role in the regulation of Bak and Bax apoptotic function, but underlying mechanisms are not fully understood. In the present article, the mechanisms of MOMP regulation mediated by VDAC2 were explored using structure-based modeling. We show that Bak, prior to an apoptotic stimulus, possesses two low-energy conformations of high shape – and polar complementarity in respect to VDAC2, resulting in two high-affinity modes of Bak binding to VDAC2, one with Bak fully residing in the cytosol and the other with Bak α9 helix inserted into the membrane. Even higher binding affinity of VDAC2 for tBid (truncated Bid/p15) was established, suggesting the tBid-mediated displacement of Bak from the VDAC2/Bak complex resulting in the formation of the VDAC2/tBid complex. The structural analysis of the interaction of this complex with Bax revealed a very high binding affinity of this complex for Bax, suggesting the recruitment of Bax to the MOM by this complex under apoptotic conditions. Besides, we revealed one more low-energy structure of Bax of high binding affinity towards the VDAC2/tBid complex and with helix α9 inserted into the membrane.     

Breathing of voltage dependent anion channel as revealed by the fractal property of its gating

The gating of voltage dependent anion channel (VDAC) depends on the movement of voltage sensors in the transmembrane region, but the actual mechanism is still not well understood. With a view to understand the phenomenon we have analyzed the current recordings of VDAC in lipid bilayer membrane (BLM) and found that the data show self-similarity and fractal characteristics. We look for the microscopic and molecular basis of fractal behavior of gating of VDAC. A model describing the oscillatory dynamics of voltage sensors of VDAC in the transmembrane region under applied potential has been proposed which gives rise to the aforesaid fractal behavior.