Development.

illustration of the highlight Free-energy methods. We are interested in the exploration of rare events in biology. Central to the scientific objectives of the Laboratoire International Associé is the development of novel computational approaches, which will allow high–performance simulations to explore biologically relevant, micro– to millisecond timescales, and be prepared for the exascale–computational era. The current simulation methodology spans timescales commonly ranging from pico– to microseconds. We aim at bridging the gap by means of methods at the confluence of importance– and enhanced–sampling algorithms. We are focusing on these two classes of methods, improving their ease of application to routine problems of biophysical relevance. In particular, we are facilitating the estimation of standard binding free energies, using a rigorous theoretical framework. Efficient construction of free-energy landscapes along chosen coarse variables is also being enhanced with the development of novel strategies, accelerating sampling of the relevant degrees of freedom with original algorithms.

Comer, J.; Gumbart, J. C.; Hénin, J.; Lelièvre, T.; Pohorille, A.; Chipot, C. The adaptive biasing force method: Everything you always wanted to know, but were afraid to ask. J. Phys. Chem. B 2015, 119, 1129-1151. Fu, H.; Shao, X.; Chipot, C.; Cai, W. Extended adaptive biasing force algorithm. An on-the-fly implementation for accurate free-energy calculations. J. Chem. Theory Comput. 2016, 12, 3506-3513.

illustration of the highlight Kinetic modeling. Concomitantly with the development of novel algorithms targeted at the exploration of rare events, we are reconciling thermodynamics and kinetics by means of Bayesian-inference schemes to build kinetic models underlying biological phenomena. Exploiting gradient-based free-energy calculations, our methodology supplies the position-dependent diffusivity, from whence mean first-passage times and rate constants can be inferred. This methodology has been recently extended to address anomalous diffusion, whereby the mean-squared displacement along the chosen coarse variable is no longer linear in time, turning to a fractional Smoluchowski description.

Comer, J.; Chipot, C.; González-Nilo, F. D. Calculating position-dependent diffusivity in biased molecular dynamics simulations. J. Chem. Theor. Comput. 2013, 9, 876-882. Comer, J.; Schulten, K.; Chipot, C. Permeability of a fluid lipid bilayer to short-chain alcohols from first principles. J. Chem. Theory Comput. 2017, 13, 2523-2532.

Applications.

illustration of the highlight Membrane proteins. Membrane proteins are the gateways to the cell and to cellular compartments. In combination with their sophisticated environment, they perform a host of functions ranging from signal transduction, transport of metabolites to energy conversion. In mammals, up to 30% of the genome encodes membrane proteins, which today, represent the primary target for drug discovery. Yet, notwithstanding their significant population in the cell wall and their importance in cellular processes, membrane proteins are markedly less well characterized than hydrosoluble ones. This imbalance can be rationalized by the strong dependence of the structure and stability of membrane proteins on their native lipid environment. For many years, we have used molecular-dynamics simulations in synergy with experiment to dissect the interplay of membrane proteins with their surroundings, focusing on members of the mitochondrial carrier family, and on the p7 protein of Hepatitis C virus, crucial for assembly and release of infectious virions. In addition to addressing the dynamics of membrane proteins in near physiological conditions, we employ molecular dynamics simulations to rationalize the information gleaned in structural biophysics experiment in mimetic environments, notably in detergents.

Dehez, F.; Pebay-Peyroula, E.; Chipot, C. Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel. J. Am. Chem. Soc. 2008, 130, 12725-12733. Zoonens, M.; Masscheleyn, S.; Comer, J.; Pebay-Peyroula, E.; Chipot, C.; Miroux, B.; Dehez, F. Mitochondrial uncoupling protein 2 in dodecylphosphocholine: Partly denatured and severely inactivated. J. Am. Chem. Soc. 2013, 135, 15174-15182.

illustration of the highlight DNA lesions and repair. DNA is constantly exposed to external threats, such as UV light, ionizing radiation and oxidative stress, that can trigger a variety of complex lesions, including base dimerization, oxidation or strand breaks. The accumulation of DNA lesions in cells can ultimately be responsible for cell death and the development of cancers or aging-associated diseases. Living organisms have developed a hand of strategies to maintain the integrity of their genome involving the recognition of a lesion in a large pool of intact nucleobases and its subsequent repair by a set of dedicated proteins. There are two essential sophisticated repair mechanisms, the nucleotide excision repair pathway, especially invoked for the removal of complex and bulky lesions and the base excision repair mechanisms. We employ all-atom molecular-dynamics simulations to predict the structural modification of DNA double-helices in response to various lesions and decipher their subsequent interactions with repair proteins.

Bignon, E.; Gattuso, H.; Morell, C.; Dehez, F.; Georgakilas, A. G.; Monari, A.; Dumont, E. Correlation of bistranded clustered abasic DNA lesion processing with structural and dynamic DNA helix distortion. Nucleic Acids Res. 2016, 44, 8588-8599. Gattuso, H.; Dumont, E.; Chipot, C. J.; Monari, A.; Dehez, F. Thermodynamics of DNA: Sensitizer recognition. Characterizing binding motifs with all-atom simulations. Phys. Chem. Chem. Phys. 2016, 18, 33180-33186.

illustration of the highlight Molecular motors. Molecular motors are nanoscale devices, which harness the free energy from chemical reactions into mechanical work with minimal dissipation. Such motors serve an important purpose in living organisms, driving conformational transitions that regulate a variety of biological processes, from RNA translocation, ATP synthesis and hydrolysis, to cytoskeletal transport. Chemists have learned lessons taught by the cell machinery and the principles of energy transduction in biological motors to design and synthesize structurally simpler, yet functionally targeted abiological devices. These devices have found applications in various areas of molecular recognition, encompassing nanosensors and transducers, which, in turn, can be employed in an automated platform for the synthesis of small molecules, defining an area of frontier research that was awarded the Nobel Prize in Chemistry in 2016. Our research focuses on molecular motors at different scales, from small abiological, cyclodextrin-based nanodevices to the large biological complexes of the respiratory chain. Using molecular-dynamics simulations, our effort aims at reconciling structural, biochemical, thermodynamic and kinetic information to render a complete, detailed picture of the processes at play. In addition, we focus on the spurious mutations and oxidative stress that affects the efficiency of the respiratory complexes, in connection with a variety of mitochondrial diseases and aging.

Liu, P.; Shao, X.; Chipot, C.; Cai, W. The true nature of rotary movements in rotaxanes. Chem. Sci. 2016, 7, 457-462. Singharoy, A.; Chipot, C.; Moradi, M.; Schulten, K. Chemomechanical coupling in hexameric protein- protein interfaces harnesses energy within V-Type ATPases. J. Am. Chem. Soc. 2017, 139, 293-310.

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

News

- 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).
 

Contact

Laboratoire International Associé
CNRS-UIUC
Unité mixte de recherche n°7565
Université de Lorraine, B.P. 70239
54506 Vandoeuvre-lès-Nancy Cedex, France
 
Phone: +33.(0)3.83.68.40.97
Fax: +33.(0)3.83.68.43.87
 
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