All these results were obtained thanks to the HPC facilities of
and the following founders
RESEARCH
I
am
are
interested
in
the
multi-scale
modeling
and
molecular
dynamics
(MD)
simulations
of
biophysical
processes.
For
my
research,
I
develop
and
use
atomistic
and
coarse-graining
MD
for
studying
protein
stability
and
function
in
different
environments
such
as
in
phospholipid
membranes
or
in
direct
or
inverted
micelles.
I
also
use
quantum
mechanical
(QM)
approaches
to
develop
force
field
parameters
for
biomolecules
(
e.g.
detergents)
widely
used
in
experiments
in
the
field
of
membrane
protein
(MP).
A
brief
description
of
my
current
research
interests
is
given
below
and
the
papers
published
from
these
research
topics
are
listed
in
the
publication
section
of
this website.
Reverse micelle systems
Reverse micelles (RM) are stable, isotropic, water microemulsions suspended in organic solvents (such as alkanes, scCO2). They were originally employed since decades for instance, with terahertz or NMR, spectroscopy techniques or MD to examine the structure and dynamics of the water and biomolecules in a confined environment mimicking the cellular interior. RMs have a great interest since they are capable to solubilize various biomolecules (such as proteins, poymers, sugars, etc.) inside their water pools. However, the solubilization or not of biomolecules depends significantly on a multitude of parameters such as the chemical nature of the surfactant, the use of cosurfactants or the water content inside the RM water pool and remain poorly understood, so far. To examine this aspect in details, we use atomistic MD and experimental approaches (e.g. time-domain THz spectroscopy, SAXS) to examine different parameters of the RM and confined water oroperties that may influence their solubilization capabilities such as the static and dynamical characteristics of the confined water, their structural changes with confined peptides, globular proteins (cytochrome C) and more recently with membrane protein (gramicidin A channel). These researches were made, in part, in collaboration with Dr. D. Laage at ENS Paris and Dr. T. Elsaesser, at U. Berlin.
Surfactant systems
Detergents (or surfactants) play an essential role in the membrane protein (MP) studies; their amphiphilic nature allows them to interact with the hydrophobic region of MPs to keep them water-soluble outside of their native bilayer environment. Unfortunately, solubility does not always “translate” to native structure and stability; a detergent that is useful for extraction may not be compatible with purification and/or biochemical studies. Furthermore, a detergent working on one membrane protein may not be suitable for a different one. Indeed, detergents are often qualitatively described as ‘harsh“ (e.g., SDS, DPC) and “mild“ (e.g., DDM and OG) based upon their relative propensity to denature proteins by interacting with non-membranous regions of proteins. Properties of detergents that render them denaturing include headgroup charge (a charged head group is more denaturing than a zwitterionic one which, in turn, is more denaturing than a neutral one), as well as acyl tail length (a shorter chain is more denaturing than a longer one). Therefore, there is not a set of “golden rules” for the use of detergents for MP applications. Understanding the physical-chemical properties associated with different classes of detergents is thus crucial for choosing which detergent may work best for a particular application. In this research, we use large scale atomistic and coarse-grained MD simulations combined with biophysical experiments such as scattering experiments (e.g. SAXS, SANS) and fluorescence spectroscopy to study structural and dynamical properties of various types of micelles with e.g. bDDM, LDAO, DPC, SDS or TX100 with often newly developped parameters and peptides, membrane proteins as well as with organic pollutants such as PAHs in the context of surfactant ehanced remediation. These researches were made, in part, in collaboration with Dr. François Yves Dupradeau U. of Amiens, France, Dr. Françoise Bonneté, IBPC, Paris or the group of Pr. Zhi Dang at the South China University of Technology, Guanzhou, China
Membrane-protein systems
Membrane proteins (MPs) play major roles in living organisms and participate to exchanges and communications between cells and their immediate environment as receptors, transporters, ion channels, etc. MPs are also involved in a large number of pathologies ( e.g. influenza, HIV …) and genetic diseases ( e.g. cystic fibrosis) and theirefore their physiological and biomedical relevance makes them major targets for a large part of the pharmaceutical molecules in development. Despite their importance, the 3D structures at atomic level of MPs represent barely 2% of biological macromolecular structures in the Protein Data Bank. This deficit is due to difficulties in the preparation of suitable samples for structural studies by NMR, cryo-EM or crystallography. Indeed, these structural techniques require the use of membrane-mimetic environments, such as detergents, amphipathic polymers or nanodiscs, to extract proteins from their native lipidic environments and to keep them stable, functional and monodisperse. For instance, in the case of crystallography, growing well-ordered diffracting crystals directly from detergent solutions remains the most largely used method, because of its ease of implementation similar to soluble proteins (vapor diffusion, batch, dialysis). However, this crystallization method is very dependent on the nature of the detergent used and thus remain nowadays challenging in particular for choosing the good detergent. In this context, we use large scale MD simulations combined with experimental approaches (SAXS, SANS, SEC-MALLS) to gain insights into how the selected detergent buoy mimic the natural membrane and influence MP properties is essential. Recent results were obtained for large MPs such as the light harvesting complex type 2 from a purple bacteria Rps. acidophila or with the TonB MP protein (ShuA) from Shigella dysenteriae . These activities of research is done, in part, in collaboration with Dr. Françoise Bonneté, IBPC, Paris
Models
of
the
MP
ShuA
inserted
in
DDM
micelles
with
various
numbers
of
surfactants
or
in a gram-negative bacteria outer membrane.
Made with Magix
© st-abel.com. Tous droits réservés 2021
Developments of force fields for biomolecules
Most
of
the
empirical
force
fields
used
in
classical
MD
simulations
use
the
fixed-charge
model
when
computing
electrostatic
forces
and
energies.
In
this
approach,
a
single
value
for
the
atomic
charge
is
assigned
to
each
atom
independently
of
the
electrostatic
environment.
Atomic
partial
charges
are
derived
and
validated
by
using
both
experimental
data
and
QM
calculations
and
e
ach
force
field
provides
its
own
set
of
atomic
charges
for
standard
residues
or
other
biolecules
(e.g.
nucleaic
acids,
surfactant,
etc.)
in
its
specific
format.
The
“problem”
of
the
atomic
partial
charges
is
that
they
are
not
observables
as
is
an
electron
density
and
that
there
are
no
standard
criteria
to
evaluate
the
quality
of
them.
It
has
been
required
that
the
charges
should
be
independent
of
the
computational
methods,
QM
basis-sets,
conformations
of
the
molecule
and
should
be
transferable
and
conform
to
the
atom
electronegativity.
There
exist
several
different
methods
for
deriving
partial
charges
such
as
Mulliken,
Löwdin
population
analysis
or
empirical
approaches
to
reproduce
crystallographic
or
liquid
data
(e.g.,
liquid
data,
or
crystal
properties
),
the
electrostatic
potential
(ESP)
derived
charges
using
semi-empirical
or
ab-
initio
methods
and
the
AM1-BCC
approach.
Unfortunately,
none
of
the
charge
models
has
proved
to
be
the
best
in
all
respects.
For
instance
in
case
of
the
ESP
charges
are
not
easily
transferable
between
common
groups
of
homologous
molecules
and
depends
significantly
on
molecular
orientation
and
conformation.
In
collaboration
with
Dr
François
Dupradeau
(Unversité
of
Amiens,
France),
we
used
the
“building
blocks”
approach
implemented
in
the
REDserver
(
https://upjv.q4md-forcefieldtools.org/REDServer-
Development/
)
where
a
complex
molecule
(i.e.
with
different
chemical
groups)
is
split
into
different
elementary
chemical
fragments
with
well-defined
and
controlled
conformations.
This
approach
has
many
advantages
over
the
whole
molecule
approach
to
derive
RESP
charges:
(i)
the
computational
time
required
for
geometry
optimization
and
molecular
electrostatic
potential
(MEP)
computation
is
drastically
reduced,
(ii)
the
optimized
geometry
of
the
conformation(s)
of
each
molecular
fragment
is
fully
defined
and
controlled,
(iii)
optimized
conformations
presenting
intramolecular
hydrogen
bonds
are
discarded
from
charge
derivation
to
avoid
over-polarization
effects,
and
finally
(iv)
a
large
set
of
analog
molecules
can
be
simultaneously
involved
in
charge
derivation
leading
to
a
homogeneous
Force
Field
Topology
DataBase
(
FFTopDB
).
This
approach
was
successfully
used
to
obtain
RESP
atomic
partial
charges
for
various
biomolecules
used
in
my
MD
simulation
works
including
glucose
polymers,
photosynthetic
pigments,
modified
amino-
acids,
and
various
types
of
surfactant
fully
compatible
with
the
Amber
force
fields
for
proteins and sugars.
Models
of
a
pure
LDAO
micelles
and
a
fragment
of the lipid kinase PIK4A (DI)
Models
of
aggregation
process
of
two
AOT
RMs
in isooctane with W
0
=5
Glycolipid based membrane systems
Bio-glycolipids prepared from the modified strain S. bombicola ΔugtB1 commonly called glucolipids (GL) present several interesting properties that can be useful for the development of several types of materials such as: hydrogels, vesicles, ultra-resistant foams, development of biocidal surfaces, stabilizers of nanoparticles for applications in the biomedical field, etc... Acidic glucolipid, characterized by a COOH group and a β- glucose unit, opposite each other show astonishing properties: the spontaneous formation of interdigitated lipid membranes whose charge is variable according to the pH. It has also been shown that the nature of the COOH group plays a very important role, in particular for the contribution of a negative charge which has the role of softening the elastic properties of the membrane. The effects of the pH and ions on these characteristics are not well understand, so far. To gain insights into these aspects and in particular their mechanical properties, MD simulations are used with various neutron scatterings approaches. T hese activities of research is done in collaboration with Dr. Niki Baccile, Laboratoire de Chimie de la Matière Condensée de Paris, Sorbonne Université, CNRS et Collège de France
RESP
charge
derivation
for
the
α-
and
β-anomers
of
glycolipids
using
the
bulding
block
approach
and
applying
INTRA-
and
INTER-MCC
constraints
during
the
fitting
step
are
represented
using
fine
dashed
and
dashed
lines,
respectively.
This
allows
defining
the
molecular
fragments
required
for
the
construction
of
the
α-
and
β-anomers
of
DDM -surfactants.
Coarse
grained
model
of
a
interdigitated
membrane.with
100%
of
protonaned
glycolipids
The
glucose
and
COOH
heads
are
in
yellow
and
red,
respectively
whereas
the
alkyl
chain
is
in
grey color.
