Computational Analyses of the Molecular Behaviour of Membrane Proteins

  • Victoria Oakes

Student thesis: Doctoral ThesisPhD


Membrane proteins are proteins which are embedded in (integral membrane proteins) or interact with (peripheral membrane proteins) the plasma membrane. Membrane proteins are responsible for a wide-range of processes, including transport, signalling and enzymatic reactions. Ion channels are an important class of membrane protein which enable the passive diffusion of ions
across the membrane. G-protein coupled receptors are another class of membrane protein which propagate chemical signals between the cell interior and exterior. There is substantial interest in understanding the molecular behaviour of such membrane proteins in a physiological and pharmaceutical context, in order to discern how they function and how they can be regulated
when they function incorrectly. Simulation methods, such as classical molecular dynamics, are can be employed for this purpose. This thesis details the use of molecular dynamics simulations, and related simulation methods, to analyse phenomena related to membrane transport by ion channels and G-protein coupled receptors.
Principally, research presented in this thesis has unveiled several novel aspects concerning the molecular behaviour of K+-channels. The size and dynamics of openings in the surface of ion channels, known as fenestrations, has been assessed in several K+-channels to delineate their potential as drug access pathways. By analyses of the archetypal K+-channel KcsA, a bacterial K+-channel, and an atypical K+ -channel, TWIK-1, from the two-pore domain K+-channel family, specific residues in the domain of the selectivity filter have been shown to be important in maintaining the structural stability of the selectivity filter and/or facilitating quintessential conduction processes. Moreover, the molecular mechanism pairing the dynamics of the KcsA selectivity filter and phospholipid molecules bound on the channel surface has been outlined.
Simulation methods have also been applied to structures of other membrane proteins, which have been recently resolved at high-resolution, by either cryo-electron microscopy or X-ray crystallography. The interfacial regions between the transient receptor potential vanilloid channel 1 (TRPV1) and several protein assemblies have been predicted. Furthermore, cholesterol-phospholipid and cholesterol-protein complexes have been characterized, in order to assess the functional effect of membrane cholesterol on the activation state on the 5-HT1B and 5-HT2B G-protein coupled receptors.
Date of Award3 Apr 2019
Original languageEnglish
Awarding Institution
  • University of Bath
SponsorsBiotechnology and Biological Sciences Research Council
SupervisorCarmen Domene (Supervisor) & Ian Williams (Supervisor)

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