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[交流] Postdoctoral position in theoretical physics/biophysics (France)

Postdoctoral position in theoretical physics/biophysics
Theory of the dynamics of DNA conformational changes. Comparison with Tethered Particle Motion experiments
par Manoel Manghi - 15 octobre
Contact : Manoel Manghi, manghi@irsamc.ups-tlse.fr
Nicolas Destainville destain@irsamc.ups-tlse.fr
Laboratoire de Physique Théorique, Université de Toulouse and CNRS, France, www.lpt.ups-tlse.fr

The dynamics of DNA conformations induced by mechanical or biochemical constraints is a central issue for biologists and remains challenging for physicists. Indeed, on the biological point of view, it directly concerns the understanding of replication and transcription in vivo, which are out-of-equilibrium active processes.

Tethered Particle Motion (TPM) experiments, which are good candidates for exploring the local DNA dynamics in presence of its partner proteins, are developed in L. Salomé’s group of the IPBS in Toulouse [1]. Based on the tracking of a nano-particle attached to the free end of a DNA molecule immobilized by the other end on a surface, the TPM technique reveals the conformational dynamics of the DNA molecule [1, 2]. In particular, it has proved to provide a reﬁned characterization of DNA-protein interactions. Recently, Salomé’s group has succeeded in developing a single-DNA chip integrating the TPM technique that makes possible massive parallel measurements [3]. On the theoretical side, DNA dynamics is usually modeled using the classical Rouse dynamics (or Zimm one, if hydrodynamic interactions are taken into account) [4], where DNA is seen as a simple polymer without internal structure. Although this approach is valid on length scales larger than 100 base-pairs, it fails at the smaller scale of interest, where taking the double helical structure into account becomes essential. Moreover, the dynamics becomes much more complex as soon as counterions, hydrodynamics interactions, external constraints (external or induced by partner proteins) are considered.

The theoretical work, to which the candidate will contribute, consists in elucidating a number of issues concerning the intra-chain DNA dynamics which might be observable in TPM experiments. The candidate will focus on the inﬂuence of local elastic properties (which varies with the local base-pairing state [5]) on the looping dynamics. For instance, it has recently been proposed [6] that the extremely slow closure of DNA denaturation bubbles (local DNA segments where base-pairs are broken), observed in experiments, is essentially due to a metastable barrier associated to the bending energy stored in the bubble (which is much more ﬂexible than the double-helix segments). This metastable state is relaxed once the double-helix strands have diﬀused towards an aligned state. Such activation barriers might also play a central role in protein-DNA complexation, which are kinetically controlled. Types of questions that await answers are : How does the DNA local elasticity modify reaction rates ? How does the geometric constraint induced by proteins on DNA in synaptic complexes contribute to reactions rates and equilibrium constants ? Is the formation of local bubbles in constrained DNA a limiting step ? The experimental studies by TPM on the Xer-dif synapse (collaboration with biologists F. Cornet and P. Rousseau [2]) and the DNA looping by Lac repressor might be a challenging context for such a theoretical study.

The theoretical methods used in this study will be both standard analytical tools of non-equilibrium statistical physics (Langevin equation, mean ﬁrst passage time, hydrodynamic interactions) and polymer physics (Worm-Like Chain model, transfer matrices), and numerical simulations (Kinetic Monte-Carlo, Brownian dynamics) [2, 7].

The candidate will join the Statistical Physics group of the Theoretical Physics Laboratory and participate to the “TPM-on-a-chip” ANR project in which is granted this two-years postdoctoral position starting on 1st semester of 2013. An eﬀort will be made on the comparison with experiments done by the biophysicists involved in this pro ject (Salomé’s group at IPBS and R. Phillips’ group of California Institute of Technology).

The salary will be of about 2040€ per month (2650$) (before income taxes, after social taxes) and the candidate will beneﬁt from the French health insurance (Sécurité Sociale) and employment beneﬁts.

Applicants should send their application letter along with their Curriculum Vitæ and publication list before March 1st, 2013. Recommendation letters are welcome.

References :
[1] N. Pouget, C. Turlan, N. Destainville, L. Salomé, M. Chandler. IS911 transpososome assembly as analysed by tethered particle motion, Nucl. Acids Res. 34 4313 (2006).
[2] M. Manghi, C. Tardin, P. Rousseau, J. Baglio, L. Salomé, N. Destainville, Probing DNA conformational changes with high temporal resolution by tethered particle motion, Phys. Biol. 7 046003 (2010).
[3] T. Plenat, C. Tardin, P. Rousseau, L. Salomé, High-throughput single-molecule analysis of DNA-protein interactions by tethered particle motion, Nucl. Acids Res. 40 e89 (2012).
[4] M. Doi, S.F. Edwards, The theory of polymer dynamics, Clarendon Press, 1986.
[5] J. Palmeri, M. Manghi, N. Destainville, Thermal denaturation of ﬂuctuating DNA driven by bending entropy, Phys. Rev. Lett. 99 088103 (2007).
[6] A.K. Dasanna, N. Destainville, J. Palmeri, M. Manghi, Strand diﬀusion-limited closure of denaturation bubbles in DNA, EPL 98 38002 (2012).
[7] M. Manghi, X. Schlagberger, Y.-W. Kim, R.R. Netz, Hydrodynamics eﬀects in driven soft matter, Soft Matter 2 653 (2006).

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