Project Title : Enhanced molecular dynamics simulations of PEGylated agonist and antagonist

binding to cardiac β-adrenergic receptors

Supervisor : Pr T.p HA-DUONG

Laboratory : BioCIS, Universit. Paris-Saclay, 17 avenue des Sciences, 91400 Orsay, France

Duration : 18 months, starting January 2024

Project Description :

In the framework of an ANR project, named CARDIOPEG, the objective of the proposed

research will be to characterize and compare the interactions of PEGylated ligands versus free

ligands with β-adrenergic receptors (β-ARs), by using enhanced molecular dynamics (MD)

simulations of their binding and unbinding processes.

The cell membrane of cardiac myocytes is characterized by invaginations of the surface membrane,

occurring primarily perpendicular to myocyte longitudinal edges, that form a complex

interconnected tubular network penetrating deep into the cell interior (Fig. 1A). Like the cardiac

cell outer surface membrane (OSM), the transverse tubule membrane (TTM) contains

many receptors, channels or enzymes, including β-ARs which are key players in the regulation

of cardiac function. Nevertheless, biochemical assays have provided indirect evidence that

β-ARs may have different properties and/or activity whether located in TTM or OSM [1].

Classical pharmacology using β-AR agonists or antagonists allows to explore the function of

β-ARs in the whole cell membrane but not separately in OSM versus TTM compartments.

Therefore, chemistry and biology collaborators have developed PEGylated ligands that can

differentiate the function of β-ARs according to their location on the cell membrane : While

free agonists or antagonists have access to all cell membrane (OSM+TTM), a PEGylated

ligand will only access to OSM due to its increased size which prevents it to penetrate the

TT network (Fig. 1B). This innovative chemical biology tool will allow to characterize and

compare the respective roles of OSM versus TTM β-ARs in intact cardiomyocytes.

However, the precise mechanism of action of PEGylated agonists or antagonists of β-ARs is

not known compared to that of their free counterparts. In particular, the impact of the PEG 

chain on the ligand binding to the activation site and on the activated receptor conformational

dynamics have never been documented to date. In this context, we propose to employ enhanced

MD simulations, including steered MD and umbrella sampling, to investigate the binding

process of five PEGylated ligands to β-ARs and the latter conformational response. Receptors

will be embedded within explicit lipid bilayers and all biomolecules will be solvated by explicit

water molecules and ions. MD simulations will be performed with the CHARMM36m force

field [2] and the GROMACS software [3]. The postdoctoral research will provide valuable

information at the atomic scale about the structure-dynamics-activity relationship of β-ARPEG-

ligand complexes.

Profile : Candidates must have a PhD in computational biophysics or biochemistry with

strong skills in molecular dynamics (MD) simulations.

Application : tap.ha-duong@universite-paris-saclay.fr (attach a single PDF file including

cover letter, curriculum vitae, and list of publications).

[1] Barth., M. ; Lefebvre, F. ; Langlois, E. ; Lefebvre, F. ; Lech.ne, P. ; Iturrioz, X. ;

Llorens-Cortes, C. ; Ha-Duong, T. ; Moine, L. ; Tsapis, N. ; Fischmeister, R. Distinct

functions of cardiac β-adrenergic receptors in the T-tubule vs. outer surface membrane.

bioRχiv 2022. doi :10.1101/2021.04.28.441732.

[2] Huang, J. ; Rauscher, S. ; Nawrocki, G. ; Ran, T. ; Feig, M. ; de Groot, B.L. ; Grubmu?ller,

H. ; MacKerell, A.D. CHARMM36m : an improved force field for folded and

intrinsically disordered proteins. Nature Methods 2017, 14, 71–73.

[3] Abraham, M.J. ; Murtola, T. ; Schulz, R. ; P.ll, S. ; Smith, J.C. ; Hess, B. ; Lindahl, E.

GROMACS : High performance molecular simulations through multi-level parallelism

from laptops to supercomputers. SoftwareX 2015, 1–2, 19–25.