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Séminaire impromptu - Maria Musgaard Structures in motion – using computer simulations to understand brain receptor function (Interview for group leader position in Bordeaux)

Abstract :


 Advances in structural biology has provided us with a wealth of atomic-resolution structural information for membrane proteins,
including receptors in the central nervous system. These structures can be seen as static snapshots of the receptor, and although much can be learnt from such snapshots, one often needs to study the dynamics to get a better understanding of how the receptor works, how mutations affect receptor function or how modulators exert their effect. Using computer simulations to predict receptor dynamics, we can obtain high resolution in space and time simultaneously and thus bridge static structural and dynamic functional data.

I will discuss some of our recent work, focussing on understanding the function and modulation of ionotropic glutamate receptors (iGluRs). By combining simulation studies with electrophysiology, we have e.g. described an unanticipated role of sodium ions in regulating kainate receptors (Nat. Struct. Mol. Biol. 2013), and for AMPA receptors identified a structural motif crucial for activation for the “naked” receptor but only of minor importance in the presence of auxiliary subunits (Neuron 2016). Furthermore, we have demonstrated that a cheap simulation method can predict stabilising or destabilising effects of iGluR mutations (J. Chem. Inf. Model. 2016). I will furthermore touch upon some of my ongoing work on acid-sensing ion channels, where we are seeking to understand how the acid sensors control channel gating.

Selected publications

Last publications..

1.Insights into channel dysfunction from modelling and molecular dynamics simulations.
Musgaard M, Paramo T, Domicevica L, Andersen OJ, Biggin PC.
Neuropharmacology. 2017 Jun 29. pii: S0028-3908(17)30303-9. doi: 10.1016/j.neuropharm.2017.06.030. [Epub ahead of print] Review.

2.
Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors.
Alcaino C, Musgaard M, Minguez T, Mazzaferro S, Faundez M, Iturriaga-Vasquez P, Biggin PC, Bermudez I.
J Biol Chem. 2017 Jan 13;292(2):551-562. doi: 10.1074/jbc.M116.751206. Epub 2016 Nov 18.


3.
Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
Musgaard M, Biggin PC.
J Chem Inf Model. 2016 Sep 26;56(9):1787-97. doi: 10.1021/acs.jcim.6b00297. Epub 2016 Aug 12.

4.
Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes.
Dawe GB, Musgaard M, Aurousseau MR, Nayeem N, Green T, Biggin PC, Bowie D.
Neuron. 2016 Mar 16;89(6):1264-76. doi: 10.1016/j.neuron.2016.01.038. Epub 2016 Feb 25.

Scientific focus :

Background
I obtained my BSc, MSc and PhD degrees in Medicinal Chemistry from Aarhus University, Aarhus, Denmark. My PhD research focused mainly on molecular dynamics simulations of the calcium ATPase from sarco(endo)plasmic reticulum, SERCA, in close collaboration with the crystallography group at the PUMPkin research centre.


Research
My current research focuses on receptor dynamics with a particular emphasis on the ionotropic glutamate receptors. We are especially seeking to describe how the ion channel opens, and how this event is coupled to the preceding ligand binding.
The work is supported by the Leverhulme Trust.