Transport phenomena across membranes.
illustration of the highlight Mitochondrial transport. In collaboration with the Institut de Biologie Structurale in Grenoble, we attempt to decipher the molecular mechanisms whereby the ADP/ATP carrier conveys across the mitochondrial membrane the ADP/ ATP tandem. We have brought to light the unique topology of the electric field created by the protein, which forms an electrostatic funnel capable of attracting the substrate towards the bottom of the internal cavity of the carrier (Dehez et al. 2008). We have also shown how in a high-concentration saline environment saturation of the basic patches of the mitochondrial carrier hampered binding of the nucleotides, hence abolishing transport (Krammer et al. 2008).

illustration of the highlight Translocon. The role of the membrane complex SecY, or translocon, is to guide at the level of the endoplasmic reticulum membrane proteins that have been generated by the ribosome. The latter anchors on the SecY complex, thereby forming a continuum between the exit tunnel and the transmembrane channel. In collaboration with the University of Illinois, we have established that the translocon represents an environment intermediate between water and membrane, hence reducing the energetic cost for translocating charged amino acids, as well as the gain for the passage of highly hydrophobic side chains (Gumbart et al. 2011). We have further confirmed that while the behavior of the nascent chain in the translocon is similar to that in bulk water, the bottleneck located in the midst of SecY favors entropically self-organization of secondary structures (Gumbart et al. 2011).

illustration of the highlight Replication of the Hepatitis C virus. p7 is a small membrane protein, which belongs to the replication apparatus of Hepatitis C virus and forms through oligomerization ion channels in the membrane of the endoplasmic reticulum. In collaboration with the Institut de Biologie et Chimie des Protéines in Lyon, we have determined the three-dimensional structure of p7 in its monomeric state by combining 1H and 13C NMR experiments and molecular-dynamics simulations (Saint et al. 2009, Montserret et al. 2010).

Supramolecular assemblies.
illustration of the highlight Cyclodextrin-based complexes. In collaboration with Nankai University, we investigate supramolecular architectures, the building block of which is a cyclodextrin. Taking advantage of recent developments in the field of free-energy calculations, we have established, for instance, the optimal arrangement of two cyclodextrins forming a [3]rotaxane (Yu et al. 2008) and deciphered the shuttling mechanism of a cyclodextrin between the two stations of a [2]rotaxane (Liu et al. 2010). We have also rationalized the recruitment of drugs by cyclodextrins (Cai et al. 2009).

illustration of the highlight  Solubilizing carbon nanotubes. One of the grand challenges of supramolecular organic chemistry is the solubilization of carbon nanotubes, which are notoriously insoluble. In partnership with Nankai University, we have shown how a chain of alginic acid associates reversibly with such tubular structures (Liu et al. 2010). Following a similar approach, we have also examined how a chitosan chain could wrap around a carbon nanotube, paving the way to promising strategies for gen therapy (Liu et al. 2011).

Interaction with the biological membrane.
illustration of the highlight Photosynthetic apparatus. One of the conundrums of the self-organization of the bacterial photosynthetic apparatus, in particular the assembly of the light-harvesting complex I (LH1) and the reaction center (RC), is the role played by a protein named PufX. In collaboration with the Uni versity of Illinois, we have proposed that PufX may form glycophorin A-like dimers and further suggested that such dimers might be the nucleation point of dimerized LH1:RC complexes, lying at its center (Hsin et al. 2009, 2011).
illustration of the highlight Aquaporins. GlpF, the facilitator of glycerol transport belongs to a family of membrane proteins, the aquaporins, investigated by Peter Agre, 2003 Nobel prize winner in chemistry. Employing free-energy calculations along a model reaction coordinate, we have followed the diffusion of a glycerol molecule in the channel of GlpF and shown that, on the one hand, transport and, on the other hand, isomerization and reorientation, span comparable time scales. A kinetic model suggests that glycerol diffusion appears as a slow process only on account of the many failed attempts of the permeant to cross the selectivity filter (Hénin et al. 2008).
illustration of the highlight Free-energy methods. Determination of free energy differences can follow three possible routes: (i) Estimation from probability distributions, (ii) direct computation, and (iii) evaluation of the free energy derivative over some order parameter and its subsequent integration. We are focusing on the latter two classes of methods, improving their ease of application to routine problems of biophysical relevance. In particular, we are facilitating the design of site-directed mutagenesis experiments within the framework of free energy perturbation. Efficient construction of free energy profiles along a chosen order parameter, ideally a reaction coordinate, is also being enhanced in the development of novel strategies relying on the evaluation of the free energy derivative and the continuous estimate of the biasing force required to overcome the free energy barriers.
illustration of the highlightSolubiliy calculations. Estimation of solubilities constitutes a challenge from the perspective of numerical simulations. While the solvation aspect can be in prinicple handled easily with a reasonable accuracy by means, for instance, of a perturbative approach, the contribution of the solid is far more difficult to tackle. In particular, taking into account the reorganization of the solid in response to the removal of a molecule appears to be daunting from the standpoint of statistical simulations. We have proposed an approach that allows the solubility of a solid to be determined numerically in different solvents by combining the experimental measurement of the solubility in one solvent with solvation free-energy calculations (Chebil et al. 2010).
illustration of the highlight Polarization phenomena. Pairwise additive potential energy functions utilized for the simulation of biological systems rely on an implicit and, hence, incomplete treatment of electronic polarization. However effective for a wide range of applications, these force fields rapidly reach their limitations when induction phenomena are significant. To address this issue, an approach has been devised, relying on the derivation of distributed polarizabilities from induction energy maps determined quantum mechanically. The resulting models of implicitly interacting atomic polarizabilities are now being incorporated into potential energy functions and probed in geometry optimization calculations, e.g. cation-π interactions.

Recent publications

The lubricating role of water in the shuttling of rotaxanes
Haohao Fu; Xueguang Shao; Christophe Chipot; Wensheng Cai;
Chem. Sci. (2017) 139 (7): 293-5094

The Extended Generalized Adaptive Biasing Force Algorithm for Multidimensional Free-Energy Calculations
Tanfeng Zhao; Haohao Fu; Tony Lelievre; Xueguang Shao; Christophe Chipot; Wensheng Cai;
Journal of Chemical Theory and Computation (2017) 13 (4): 1566-1576

Tribute to Klaus Schulten
Emad Tajkhorshid; Christophe Chipot;
The Journal of Physical Chemistry B (2017) 121 (15): 3203-3205


- Renewal of the Laboratoire International Associé CNRS-University of Illinois at Urbana-Champaign on November 2016
- An update of ParseFEP is available in the latest version of VMD.
- 新的分子动力学讲义 (Dissemination).


Laboratoire International Associé
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