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• W46069811 abstract "Ion channels are protein molecules, embedded in the lipid bilayer of the cellmembranes. They act as powerful sensing elements switching chemicalphysicalstimuli into ion-fluxes. At a glance, ion channels are water-filledpores, which can open and close in response to different stimuli (gating), andone once open select the permeating ion species (selectivity). They play acrucial role in several physiological functions, like nerve transmission,muscular contraction, and secretion. Besides, ion channels can be used intechnological applications for different purpose (sensing of organicmolecules, DNA sequencing). As a result, there is remarkable interest inunderstanding the molecular determinants of the channel functioning.Nowadays, both the functional and the structural characteristics of ionchannels can be experimentally solved. The purpose of this thesis was toinvestigate the structure-function relation in ion channels, by computationaltechniques. Most of the analyses focused on the mechanisms of ionconduction, and the numerical methodologies to compute the channelconductance. The standard techniques for atomistic simulation of complexmolecular systems (Molecular Dynamics) cannot be routinely used tocalculate ion fluxes in membrane channels, because of the highcomputational resources needed. The main step forward of the PhD researchactivity was the development of a computational algorithm for thecalculation of ion fluxes in protein channels. The algorithm - based on theelectrodiffusion theory - is computational inexpensive, and was used for anextensive analysis on the molecular determinants of the channelconductance.The first record of ion-fluxes through a single protein channel dates back to1976, and since then measuring the single channel conductance has becomea standard experimental procedure. Chapter 1 introduces ion channels, andthe experimental techniques used to measure the channel currents. Theabundance of functional data (channel currents) does not match with anequal abundance of structural data. The bacterial potassium channel KcsAwas the first selective ion channels to be experimentally solved (1998), andafter KcsA the structures of four different potassium channels were revealed.These experimental data inspired a new era in ion channel modeling. Oncethe atomic structures of channels are known, it is possible to definemathematical models based on physical descriptions of the molecularsystems. These physically based models can provide an atomic descriptionof ion channel functioning, and predict the effect of structural changes.Chapter 2 introduces the computation methods used throughout the thesis tomodel ion channels functioning at the atomic level.In Chapter 3 and Chapter 4 the ion conduction through potassium channels isanalyzed, by an approach based on the Poisson-Nernst-Planckelectrodiffusion theory. In the electrodiffusion theory ion conduction ismodeled by the drift-diffusion equations, thus describing the iondistributions by continuum functions. The numerical solver of the Poisson-Nernst-Planck equations was tested in the KcsA potassium channel (Chapter3), and then used to analyze how the atomic structure of the intracellularvestibule of potassium channels affects the conductance (Chapter 4). As amajor result, a correlation between the channel conductance and thepotassium concentration in the intracellular vestibule emerged. The atomicstructure of the channel modulates the potassium concentration in thevestibule, thus its conductance. This mechanism explains the phenotype ofthe BK potassium channels, a sub-family of potassium channels with highsingle channel conductance.The functional role of the intracellular vestibule is also the subject ofChapter 5, where the affinity of the potassium channels hEag1 (involved intumour-cell proliferation) and hErg (important in the cardiac cycle) forseveral pharmaceutical drugs was compared. Both experimentalmeasurements and molecular modeling were used in order to identifydifferences in the blocking mechanism of the two channels, which could beexploited in the synthesis of selective blockers. The experimental datapointed out the different role of residue mutations in the blockage of hEag1and hErg, and the molecular modeling provided a possible explanation basedon different binding sites in the intracellular vestibule.Modeling ion channels at the molecular levels relates the functioning of achannel to its atomic structure (Chapters 3-5), and can also be useful topredict the structure of ion channels (Chapter 6-7). In Chapter 6 the structureof the KcsA potassium channel depleted from potassium ions is analyzed bymolecular dynamics simulations. Recently, a surprisingly high osmoticpermeability of the KcsA channel was experimentally measured. All theavailable crystallographic structure of KcsA refers to a channel occupied bypotassium ions. To conduct water molecules potassium ions must beexpelled from KcsA. The structure of the potassium-depleted KcsA channeland the mechanism of water permeation are still unknown, and have beeninvestigated by numerical simulations. Molecular dynamics of KcsAidentified a possible atomic structure of the potassium-depleted KcsAchannel, and a mechanism for water permeation. The depletion frompotassium ions is an extreme situation for potassium channels, unlikely inphysiological conditions. However, the simulation of such an extremecondition could help to identify the structural conformations, so thefunctional states, accessible to potassium ion channels.The last chapter of the thesis deals with the atomic structure of the !-Hemolysin channel. !-Hemolysin is the major determinant of theStaphylococcus Aureus toxicity, and is also the prototype channel for apossible usage in technological applications. The atomic structure of !-Hemolysin was revealed by X-Ray crystallography, but several experimentalevidences suggest the presence of an alternative atomic structure. Thisalternative structure was predicted, combining experimental measurementsof single channel currents and numerical simulations.This thesis is organized in two parts, in the first part an overview on ionchannels and on the numerical methods adopted throughout the thesis isprovided, while the second part describes the research projects tackled in thecourse of the PhD programme. The aim of the research activity was to relatethe functional characteristics of ion channels to their atomic structure. Inpresenting the different research projects, the role of numerical simulationsto analyze the structure-function relation in ion channels is highlighted." @default.
• W46069811 created "2016-06-24" @default.
• W46069811 creator A5022820593 @default.
• W46069811 date "2008-04-18" @default.
• W46069811 modified "2023-09-27" @default.
• W46069811 title "Computational analyses on the structure-function relation inion channels" @default.
• W46069811 doi "https://doi.org/10.6092/unibo/amsdottorato/676" @default.
• W46069811 hasPublicationYear "2008" @default.
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