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Title: Voltage sensors, toxins & membranes : a simulation study
Author: Wee, Chze Ling
ISNI:       0000 0001 3565 2429
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2008
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Molecular dynamics (MO) simulations were used to study the interaction of voltage-gated potassium (Kv) channel toxins with lipid bilayers. The toxins studied were YSTx1 (Yoltage Sensor Toxin 1) and SGTx1 (Seodm griseipes Toxin 1), gating-modifier toxins from tarantula venom that bind to the voltage sensors (YS) of Kv channels and inhibit the channels by altering the energetics of voltagedependent gating. The mechanism of interaction and the depth of binding of these toxins with lipid bilayers is of interest in the context of structural models of voltage-dependent gating in Kv channels. In particular, characterizing the interaction of these toxins with lipid bilayers provided insights into the structure and dynamics of the YS of Kv channels. Atomistic (AT) MO simulations were used to localize YSTx1 and SGTx1 in lipid bilayers. Both toxins preferred a location close to the ·membrane/water interface consistent with their amphipathic molecular surface. The nature of the interactions that stabilized the toxins in the membrane was investigated. ExtendedMOsimulations with a coarse-grained (CG) protein and lipid model revealed dynamic toxin partitioning of SGTx1 from bulk water to the membrane/water interface. CG MO simulations with a total simulation time of > 30 ps were used to estimate the 10 potential of mean force (PMF) profile of YSTx1 along the bilayer normal of lipid bilayers. The PMF profiles suggest it is energetically favorable for YSTx1 to partition from bulk water to the membrane/water interface. The bilayer deformed as it interacted with the toxin, and bilayer deformation influenced the PMF profiles. AT MO simulations with a total simulation time of > 1.6 ps were also used to estimate the 10 PMF profile of YSTx1 along the bilayer normal. A novel approach was taken whereby information derived from the CG MO simulations were used to initialize the AT MO simulations. Comparisons were· made between the CG and AT PMF profiles, and that derived from an implicit membrane/solvent model. CG MO simulations were used to estimate an angular PMF profile of a 54 helix (which carries the gating charges in the YS of Kv channels) in lipid bilayers. The CG PMF profiles suggested that it is overall energetically favorable for 54 to adopt a membrane surface orientation compared to a transmembrane (TM) orientation. Interestingly, 54 could not be (meta) stably inserted in a TM orientation in membranes with reduced concentration of negatively-charged lipid phosphate moieties. Finally, CG MO simulations were performed to probe the interaction of a membrane-embedded YS with YSTx1.
Supervisor: Not available Sponsor: Not available
Qualification Name: University of Oxford, 2008 Qualification Level: Doctoral
EThOS ID:  DOI: Not available