Molecular dynamics simulations of membrane proteins in nanodiscs with investigation of protein-lipid interactions

Thesis

Membrane proteins perform various important and wide-ranging functions. They exist within a lipid bilayer and their interactions with the components of this bilayer are of great scientific and pharmacological interest due to the ability of these components to regulate protein structure and function. Computational approaches such as multiscale molecular dynamics simulations are well suited to the study of these systems. As such, the research presented here uses an array of these approaches to examine and characterise the interactions between membrane proteins and lipids in two environments: nanodiscs and lipid bilayers.

There has been exponential growth in the use of nanodiscs for solubilisation of membrane proteins in a native-like environment, where the membrane protein is embedded in a patch of lipid bilayer constrained by helical proteins. However, the impact of constraining the nanodisc components in this manner is currently not well understood. In this research molecular dynamics simulations are used to investigate these effects; the results presented here describe the changes in lipid properties which occur as a consequence of constraining the nanodisc components and subsequent variations in protein lipid interactions.

One family of membrane proteins, the G-protein-coupled receptors, was selected for further study. A simulation approach was used to examine the binding of a membrane lipid, cholesterol, to potential allosteric modulatory sites on these proteins, including the previously identified TM345 site. Interactions with cholesterol at this site were found to be common to several members of this family despite limited sequence conservation.

The results presented here demonstrate the importance of understanding the environment in which membrane proteins exist and the impact of changes to this environment upon protein behaviour, properties and interactions.

Authors: Horrell, M

• DOI: 10.5287/ora-vgv0nmzje
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Simulation; Protein-Lipid Interactions; Molecular Dynamics; Nanodiscs; Cholesterol; Coarse Grained Simulations; G-protein-coupled receptors
• Subjects: Biochemistry; Cholesterol; Methodology; Simulation methods; Nanodisc