Postdoctoral Position in Biomolecular Modeling
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.