UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Investigation of ligand selectivity and activation dynamics of G protein-coupled receptors using enhanced sampling simulations

Mattedi, Giulio; (2020) Investigation of ligand selectivity and activation dynamics of G protein-coupled receptors using enhanced sampling simulations. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[thumbnail of Giulio_Mattedi_PhD_Thesis_Revision_Final.pdf]
Preview
Text
Giulio_Mattedi_PhD_Thesis_Revision_Final.pdf - Accepted Version

Download (62MB) | Preview

Abstract

G protein-coupled receptors (GPCRs) are a large superfamily of transmembrane proteins found in eukaryotes. They play a crucial role in the transduction of signals across the plasma membrane of cells, and are involved in the regulation of a plethora of processes. Due to their function in countless biological pathways they have a primary role in many pathological conditions, and are thus therapeutic targets of great importance. Notwithstanding the growing availability of X-ray and cryo-EM structures and the intense involvement of the scientific community, many gaps are still present in our understanding of the mechanisms of ligand binding, receptor activation and allostery. Computational methods open the possibility for the study of the dynamics of such processes at atomistic resolution, complementing experimental findings. In this work key processes of a number of different GPCRs are explored with the use of computational approaches. Molecular dynamics and enhanced sampling methods are leveraged for sampling rare events of great interest and for the calculation of the associated free energy landscapes. In the first place our study of ligand binding and the selectivity mechanism in adenosine A2a and A1 receptors is reported, elucidating how selectivity arises from an interplay of structural factors. The activation mechanism of glucagon receptor and the coupling with a G protein is then investigated, highlighting the cooperative action of glucagon and G protein in the process. A detailed overview of allosteric antagonism in chemokine receptors is built by mining databases of experimental data and complementing this picture with insights on the dynamics of these receptors. Finally, the performance of TS-PPTIS (Transition State-Partial Path Transition State Sampling), a method for the calculation of kinetic rate constants, is studied for the prediction of ligand binding kinetic rates. The findings of this study add to the understanding of the mechanism of signal transduction through GPCRs, and detail this process from its origin outside the cell to the intracellular medium.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigation of ligand selectivity and activation dynamics of G protein-coupled receptors using enhanced sampling simulations
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author [year]. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: molecular dynamics, metadynamics, enhanced sampling, free energy, GPCR, glucagon, activation
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10102902
Downloads since deposit
282Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item