Journées du Centre Blaise Pascal : Exploring (Free) Energy Landscapes

Location: Salle de réunion LR6 C 023, Centre Blaise Pascal, ENS-Lyon, France
November 20th, 2012

Organizing committee:

  • Paul Fleurat-Lessard, Laboratoire de Chimie - ENS de Lyon
  • Claire Loison, Laboratoire de Spectrométrie Ionique et Moléculaire - Université de Lyon / CNRS
  • Cerasela Calugaru, Centre Blaise Pascal - ENS de Lyon

Administrative coordination:

  • Samantha Barendson, CBP, ENS de Lyon, France (samantha.barendson @

The workshop is supported by:

  • the Centre Blaise Pascal

La communauté des lyonnais utilisant l'outil numérique pour résoudre un problème scientifique est vaste : informaticiens pour sûr, mais aussi mathématiciens, biologistes, physiciens, chimistes…

L'objectif de ces rencontres est de souder cette communauté autour de rencontres conviviales. Plus concrètement, ces journées visent aussi à permettre de trouver des réponses à nos interrogations quotidiennes auprès d'interlocuteurs locaux. Que les questions soient techniques comme l'utilisation d'un logiciel par exemple, ou plus méthodologiques comme la résolution d'une équation aux dérivées partielles, au moins une réponse se trouve probablement à moins de quelques kilomètres !

Entre les objets d'étude très varies, et le processeur, hardware commun au travail de tous, se croisent de nombreux chemins qui passent par la compréhension d'un système, sa modélisation mathématique, la dérivation d'un algorithme sous-jacent, la traduction de celui-ci dans un langage, l'utilisation d'un exécutable et enfin, l'exploitation des données produites. Chacune de ces étapes peut elle-même constituer un sujet de recherche et de développement, mais certains chercheurs devront les parcourir toutes, quitte à y passer moins de temps.

Bien évidemment, les journées du Centre Blaise Pascal ne pourront balayer exhaustivement les thématiques de recherche de la communauté. Nous chercherons à présenter des applications variées, des méthodes assez générales utilisées dans différents domaines, et des matériels toujours nouveaux et toujours plus performants.

1. Program

09h30 Christophe Chipot (UHP Nancy): Addressing complex biological problems using free-energy calculations
10h30 Coffee break
10h45 Martin Spichty (ENS Lyon): Conformational free energy calculations and their application to peptide aptamer technology
11h15 Chandan Patel (ENS Lyon): Complex DNA lesions : insights from QM/MM–MD

11h45 - 14h00 Buffet Lunch

14h00 Ralf Everaers (ENS Lyon): A statistical mechanical framework for adaptive resolution multiscale simulations
15h00 Coffee break
15h15 Benjamin Bouvier (IBCP Lyon): Simulating macromolecular recognition using enhanced sampling
15h45 Pawel Koziatek (INP Grenoble): Potential energy landscape of glasses: distributions of activation energies and attempt frequencies

2. Abstracts

Christophe Chipot (UHP Nancy): Addressing complex biological problems using free-energy calculations
One of the current grand challenges of molecular modeling is the faithful description of the reaction coordinates that characterize processes of biological interest. Closely related to this endeavor, the determination of accurate free-energy changes along the model reaction coordinates constitutes an even greater challenge. Sampling the relevant degrees of freedom while circumventing hidden barriers will be illustrated in four case-studies, which demonstrate convincingly how quantitative numerical simulations based on the estimation of free-energy differences can help decipher the intricate reality of the cell machinery. The first problem revolves around the insertion of the nascent protein in the biological membrane mediated by SecY, the translocation complex, which forms a continuous channel with the exit tunnel of the ribosome. Next, the ability of bacterial cells to survive osmotic shocks will be discussed in light of our recent findings on the central role played by the cytoplasmic domain of their small-conductance mechanosensitive channels. How transmembrane segments self-assemble to form light-harvesting complexes, central to photosynthesis, constitutes the third illustration where free-energy calculations help interpret convoluted experimental data. Last, the choice of a relevant method, perturbative or gradient-based, to determine standard binding free energies will conclude this presentation.

Martin Spichty (ENS Lyon): Conformational free energy calculations and their application to peptide aptamer technology
Peptide aptamers, conceived to conceptually resemble antibodies, are man-made combinatorial protein reagents. They consist of a random sequence loop introduced into a scaffold protein (see Figure). The ends of the loop are restrained by a disulfide bond. When large libraries of random loops are expressed in living cells, certain loop sequences can adopt a conformation that is capable of interacting with a specific target protein and thereby modifying the functioning of the cell. Molecular biologists can determine the amino-acid sequence of such bioactive peptide aptamers but the three-dimensional structure remains unknown. This seminar will show how biomolecular computer simulations, such as conformational free-energy calculations can provide valuable insights into the structure of bioactive peptide aptamers, and how this information can guide biologists in their design of novel enhanced peptide aptamers.

Chandan Patel (ENS Lyon): Complex DNA lesions : insights from QM/MM–MD
DNA is continously exposed to a vast number of damaging events triggered by endogeneous and exogeneous agents.[4] Formation and structure variety of these lesions have been studied using exper- iments. Although experimental studies, within their confines, have provided very useful information regarding structural properties of some of the DNA lesions and their repair, they do not provide any mechanistic or energetic information pertaining to their formation. Computational Biochemistry has recently beneficiated from the advent of a large range methods [3], which rely on the increase of avail- able, highly-parallelized computational resources, but were first and foremost motivated by the utter need to describe as accurately as possible complex, strongly heterogeneous systems. Such multiscale and dynamical simulations have become routine for proteic systems [5], yet remain scarce on DNA. In the first seminal example in 2004, Parrinello and coworkers stressed out the importance of the B-helix environment on guanine radical cation structure. [2] QM/MM methodologies are particularly useful in this regard, as they can be used to study reaction mechanisms and electronic porperties in large systems. Here, we present our studies on oxidatively generated intrastrand crosslinks within DNA [1, 6]. In absence of NMR or X-ray structures, the B-helix distortion can be inspected purely on the basis of molecular simulations. Preliminary results obtained on other oxidative cross-link adducts, such as dCyd341, will also be discussed.[7]
References :
[1] Julian Garrec, Chandan Patel, Ursula Rothlisberger, and Elise Dumont. Insights into Intrastrand Cross-Link Lesions of DNA from QM/MM Molecular Dynamics Simulations. Journal of the American Chemical Society, 134(4):2111–2119, 2012.
[2] Francesco Luigi Gervasio, Alessandro Laio, Marcella Iannuzzi, and Michele Parrinello. Influence of DNA Structure on the Reactivity of the Guanine Radical Cation. Chemistry A European Journal, 10(19):4846–4852, 2004.
[3] Eric H. Lee, Jen Hsin, Marcos Sotomayor, Gemma Comellas, and Klaus Schulten. Discovery Through the Computational Microscope. Structure, 17(10):1295 – 1306, 2009.
[4] T. Lindahl and DE Barnes. Repair of endogenous DNA damage, 65. 2000.
[5] J.A. McCammon, B.R. Gelin, M. Karplus, et al. Dynamics of folded proteins. Nature, 267(5612):585, 1977.
[6] C. Patel, J. Garrec, C. Dupont, and E. Dumont. What singles out the G[8-5]C intrastrand DNA cross-link ? Mechanistic and structural insights from hybrid Car-Parrinello simulations. submitted.
[7] P. Regulus, B. Duroux, P.A. Bayle, A. Favier, J. Cadet, and J.L. Ravanat. Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion. Proceedings of the National Academy of Sciences, 104(35):14032, 2007.

Ralf Everaers (ENS Lyon), Rafael Delgado-Buscalioni (UAM, Madrid): A statistical mechanical framework for adaptive resolution multiscale simulations
Simultaneous multi-scale schemes directly couple parts of a system described with different models. The idea behind the embedding is to reduce finite size effects in the more finely resolved region compared to a one-level description with periodic or open boundary conditions. Classical examples are QM/MM and the reaction field method for long-range interactions. The particularity of the recently introduced AdResS scheme [1] is to allow a free exchange of particles across the interface between different regions. In the presentation, I will outline a rigorous statistical mechanical framework for the method, which we are currently developing [2].
References :
[1] M. Praprotnik, L. Delle Site, and K. Kremer, The Journal of Chemical Physics 123, 224106 (2005); M. Praprotnik, L. Delle Site, and K. Kremer, Phys. Rev. E 73, 066701 (2006); M. Praprotnik, L. Delle Site, and K. Kremer, J. Chem. Phys. 126, 134902 (2007); M. Praprotnik, L. Delle Site, and K. Kremer, Annual Review of Physical Chemistry 59, 545 (2008); L. Delle Site, S. Leon, and K. Kremer, Journal of the American Chemical Society 126, 2944 (2004); S. Fritsch, C. Junghans, and K. Kremer, J. Chem. Theory Comput. 8, 398 (2012); A. B. Poma and L. D. Site, Physical Review Letters 104, 250201 (2010); R. Potestio and L. Delle Site, J. Chem. Phys. 136 (2012); S. Poblete, M. Praprotnik, K. Kremer, and L. Delle Site, J. Chem. Phys. 132, 114101 (2010); S. Fritsch, S. Poblete, C. Junghans, G. Ciccotti, L. Delle Site, and K. Kremer, Phys. Rev. Lett. 108 (2012).
[2] R. Potestio, S. Fritsch, P. Espanol, R. Delgado-Buscalioni, K. Kremer, R. Everaers, and D. Donadio, submitted.

Benjamin Bouvier (IBCP Lyon): Simulating macromolecular recognition using enhanced sampling
Biological macromolecules do not function isolatedly, but form intricate interaction networks featuring multi-partner complexes of diverse natures and binding strengths. The mechanisms driving the recognition between partners of such complexes are very efficient yet very subtle, allowing for instance faster-than-diffusion discrimination between similar DNA sequences. They often involve a combination of chemical interactions at an interface (direct recognition) and large-scale collective motion by which each partner probes the other’s ability to deform (indirect recognition). The amplitude of motion and binding free energies involved prevent the study of such recognition processes using standard molecular dynamics simulations on current computers. In this talk, we present examples of protein-DNA, drug-DNA and protein-protein recognition processes that we have addressed using enhanced sampling simulations along custom-designed generalized coordinates. We discuss how the resulting free energy profiles and binding mechanisms help shed light on the intricacies of biomacromolecular recognition.

Pawel Koziatek (INP Grenoble), D. Rodney, J. L. Barrat: Potential energy landscape of glasses: distributions of activation energies and attempt frequencies
Molecular dynamics is a powerful tool to simulate the atomic-scale processes that occur in bulk metallic glasses either at rest during aging or under plastic deformation. This technique is however limited to short-time dynamics and does not give access to the slow thermally-activated events that progressively dominate the glass dynamics when the temperature and/or the strain rate are decreased. We report here results obtained with a saddle-point search method, the Activation-Relaxation Technique, used to determine thermally-activated paths in glasses. From the paths, we determine the distributions of activation energies and attempt frequencies, the two main parameters that characterize thermally-activated processes. We study in particular the influence by the history and level of relaxation of the glass on the above distributions.

3. Participants

Family name First name Institution
Albaret Tristan Universite Lyon 1
Bacchus Marie-Christine LASIM
Blanchet Christophe CNRS IBCP
Calugaru Cerasela ENS de Lyon
Caracas Ema ENS de Lyon
Caracas Razvan CNRS, ENS de Lyon
Cheaib Bachar ENS
Chuffart Florent CNRS
Dumont Elise Laboratoire de Chimie, ENS de Lyon
Filbet FRancis univ Lyon 1
Fleurat-Lessard Paul Laboratoire de Chimie de l'ENS de Lyon
FORSTER Georg Daniel LASIM at University Lyon 1 / Claude Bernard
Gebresilassie Abel Gebreegziabher INSA-Lyon
Giordano Valentina LPMCN
Houwaart Torsten ENS de Lyon
Ignacio Maxime LPMCN
Josh Kaustubh ENS de Lyon
Jost Daniel ENS de Lyon
Le Goff Thomas LPMCN
MERABIA Samy CNRS-université Lyon 1
Meyer Sam ENS de Lyon
Renaut Gilles-Alexis ECL LMFA
STEBE Pierre Nicolas ENS de Lyon
TANGUY Anne Université Lyon 1
VERDIER Timothée Labo de physique de l'ENS de Lyon
animation/workshops/2012/jcbp3.txt · Dernière modification: 2015/01/07 10:04 (modification externe)