Non-Equilibrium Molecular Dynamics Study of Ion Permeation through the Biological Ion Channel alpha-Hemolysin

Ion permeation properties and current-voltage (I-V) characteristics of the ion channel alpha-hemolysin (a-HL) have been calculated using non-equilibrium molecular dynamics (NEMD). In the simulation setup for our calculations, the channel was embedded in a layer of dummy atoms, which serve as an artificial membrane, and the channel structure was frozen, or held motionless throughout the simulation. This setup served to significantly reduce computational load while testing to see if realistic permeant and I-V properties for the system were maintained, by comparison to both experimental data as well as I-V data calculated using Poisson-Nernst-Planck (PNP) methodology. Additionally, diffusion constant values for both ion types inside the channel pore region were calculated using mean square displacement (MSD) methodology and compared to results for bulk solution, yielding a reduction in the diffusion constants inside the channel for each ion type of approximately one half their bulk values. While our preliminary results have produced qualitatively reasonable data, we concluded that the simulation would be more accurate if a portion of the channel structure, specifically those residues found at the protein-solvent interface, is allowed to move freely for future calculations

Computational Studies of Biological Ion Channels

Structural and functional characteristics of three biological ion channels were studied. First, current-voltage characteristics were calculated using non-equilibrium molecular dynamics (NEMD), Brownian Dynamics (BD), and Poisson-Nernst-Planck theory (PNP) for the ion channel alpha-hemolysin, comparing and contrasting the results among each other and experimental values. Results show that all methods produce qualitatively accurate results in terms of selectivity, where quantitave accuracy increases with more atomistic detailed simulation methodology. Results from NEMD simulations show that a specific location within the pore may account for selectivity of the channel, and point mutation of one residue (lys147) would likely result in a change in selectivity. The residue was mutated to serine, structural viability was tested with all-atom molecular dynamics, and PNP and BD calculations of the mutated structure show that selectivity is changed via this mutation. Second, pH dependence of current-voltage characteristics of alpha-hemolysin were studied using PNP and compared to experimental data, applying pH-dependent charge states determined from calculated pKa values for all titratable residues in the structure. Results indicate that altered charge states of both internal and external residues most accurately described experimental data. Third, Poisson-Boltzmann and (PNP) calculations were performed to determine the functional state of the crystallographic structure of the mitochondrial channel VDAC1, finding that the current-voltage properties indicated that structure represents the open conformation of the channel. Calculations were repeated using mutant channel structures, reflecting experimental results showing changes in selectivity. Two proposed gating motions of the channel were explored, with calculated current-voltage results from the gated structures not reflecting experimental changes in current-voltage properties, suggesting that the two proposed gating methods were not correct for this channel. Last, Poisson-Nernst-Planck calculations were performed of the influx of ferrous ions (Fe2+) into human H-ferritin protein. All-atom molecular dynamics simulation was used to determine both the equilibrium pore structure as well as the diffusion constant profile through the channel, using Force-Force Autocorrelation Function methodology. Results show relatively slow (compared to other channels) transit of Fe2+ ions through the channel due to greatly reduced internal diffusion constants (from bulk values) within the ferritin pore as well as low physiological concentration of Fe2+

Transient thermal recovery of a pulsed BSCCO-2223 superconducting magnet

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2000.Includes bibliographical references (p. 75-76).by Karl W. Kowallis.S.M