M2 - computation study of the sequence-dependence of the G-T mismatch appearance

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<div class="field-items"><div class="field-item odd"><p>Ecole Polytechnique, Route de Saclay, 91128 Palaiseau</p></div></div><p>&nbsp;</p>

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<p><strong>Proposal for six-month internship (M2)<br /><br />Subject: Computation study of the sequence-dependence of the G-T mismatch appearance</strong><br /><br />All living organisms strive to preserve their genetic code intact. Though polymerases copy DNA during DNA replication with remarkable accuracy, some base-pair mismatches are still incorporated at low frequency, leading to spontaneous mutagenesis[1]. As shown by recent experiments these mismatches are able to mimic the Watson-Crick base pairs in polymerases through the formation of rare tautomer and/or ionization forms[2]. During the 6-months internship, the student will focus on the sequence-dependence of mutations related to the appearance of G-T mismatches through a broad spectrum of state-of-the-art computational techniques. The student will master essential computational techniques including ab-initio methods, molecular dynamics, hybrid potential QM/MM and free energy simulations[3]. He(she) will study tautomeric forms of mismatch pairs in different sequences of DNA in solvent as well as in the DNA polymerase complex, as they appear during DNA replication. The student will also look at how the tautomer/ionization forms are bypassed and efficiently repaired by a recently discovered system, EndoMS[4]. The proposed project will be done in close collaboration with the experimental group of Dr. Hannu Myllykallio in the same research team of Ecole Polytechnique, to further validate the computational findings.<br /><br />Skills in theoretical physics and computational/structural biology or engineering/computer sciences will be considered as an asset. Previous experience with the Linux environment and basic script programming is desired, but not mandatory. For a highly motivated student the project could be extended towards a doctoral thesis on a closely related topic financed through the ANR ATMCADD grant. &nbsp;<br /><br />References:<br /><br />1. Kimsey, I. J.; Szymanski, E. S.; Zahurancik, W. J.; Shakya, A.; Xue, Y.; Chu, C. C.; Sathyamoorthy, B.; Suo, Z.; Al-Hashimi, H. M., Dynamic basis for dG*dT misincorporation via tautomerization and ionization. Nature 2018, 554 (7691), 195-201.<br />2. Wang, W.; Hellinga, H. W.; Beese, L. S., Structural evidence for the rare tautomer hypothesis of spontaneous mutagenesis. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (43), 17644-8.<br />3. Schmitt, E.; Bourgeois, G.; Gondry, M.; Aleksandrov, A., Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue. Sci. Rep. 2018, 8 (1), 7031.<br />4. Ishino, S.; Skouloubris, S.; Kudo, H.; l&#39;Hermitte-Stead, C.; Es-Sadik, A.; Lambry, J. C.; Ishino, Y.; Myllykallio, H., Activation of the mismatch-specific endonuclease EndoMS/NucS by the replication clamp is required for high fidelity DNA replication. Nucleic Acids Res. 2018.<br /><br /><br />Contact:<br />Dr. Alexey Aleksandrov,<br />Laboratoire d&#39;Optique et Biosciences<br />INSERM U1182 - CNRS UMR7645,<br />Ecole Polytechnique, Route de Saclay<br />91128 PALAISEAU CEDEX, France<br />tel: +33/(0)1 69 33 50 10<br />e-mail: Alexey.Aleksandrov@polytechnique.fr<br /><br />&nbsp;</p><br/>
Laboratoire: Laboratoire d'optique et biosciences (LOB), Ecole Polytechnique