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Computational Studies of Biological Ion Channels

Kowallis, William J (2016) Computational Studies of Biological Ion Channels. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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+.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kowallis, William Jwjkst4@pitt.eduWJKST4
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCoalson, Rob Dcoalson@pitt.eduCOALSON
Committee MemberJordan, Kenneth Djordan@pitt.eduJORDAN
Committee MemberKoehler, Peter Fkoehler@pitt.eduKOEHLER
Committee MemberWaldeck, David Hdave@pitt.eduDAVE
Date: 30 September 2016
Date Type: Publication
Defense Date: 19 July 2016
Approval Date: 30 September 2016
Submission Date: 4 August 2016
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 183
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ion channels, poisson-nernst-planck, brownian dynamics, molecular dynamics, alpha-hemolysin, ferritin, VDAC
Date Deposited: 30 Sep 2016 15:58
Last Modified: 30 Sep 2017 05:15

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