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Exploring the impact of divalent cations on ribozyme conformational fluctuations with molecular dynamics simulations

Exploring the impact of divalent cations on ribozyme conformational fluctuations with molecular dynamics simulations

By In Aiv Internship On November 6, 2019


Internship title: Exploring the impact of divalent cations on ribozyme conformational fluctuations with molecular dynamics simulations

LABORATORY
Name: Laboratoire de Biochimie Théorique
Affiliation: CNRS – Institut de BIologie Physico-Chimique
Address: 13 rue Pierre et Marie Curie 75005 Paris
E-mail: duboue-dijon@ibpc.fr

LAB Director
Name: Marc Baaden
Phone number: 0158415176
E-mail: baaden@ibpc.fr

SUPERVISOR
Name: Elise Duboué-Dijon
Phone number: 0158515181
E-mail: duboue-dijon@ibpc.fr

Subject Keywords: Molecular dynamics ; ribozyme ; RNA ; enhanced sampling ; cations

Tools and methodologies: Molecular dynamics ; enhanced sampling
Summary of lab\’s interests: Our laboratory is specialized in the simulation, at different scales, of biologically relevant processes. In particular, our team focuses on the study of biological processes mediated by divalent cations, and the development of associated simulations tools.
Project summary: RNA sequences that exhibit a catalytic activity similar to that of enzymes, called ribozymes, are found to be involved in an increasing number of biological processes. Hence, understanding the origin of their catalytic activity is a major biochemical challenge to be able to control, modify or tune their activity. [1] An intriguing question is to understand the role played by divalent cations in the ribozyme activity, their activity being related in vivo to the presence of Mg2+ ions. [2] The internship will be part of a project that aims to characterize, using molecular simulations, the molecular origin of divalent cations’ specificity in the RzB Hammerhead ribozyme catalysis. [3,4]
First, we need to determine how different cations (Mg2+, Ca2+, Na+) modulate the ribozyme conformational landscape, which will require the use of advanced sampling techniques. Since traditional non polarizable force fields do not correctly capture the interaction between (divalent) ions and RNA, different descriptions (standard non polarizable, scaled charge, or explicitly polarizable force fields) will need to be compared on small systems where experimental data are available.
The student will determine the most appropriate method to capture ion-phosphate interactions, which are key for RNA or DNA simulations in realistic biological environments. He or she will identify the binding sites and binding modes of different cations in the RzB Hammerhead ribozyme, and characterize their impact on the ribozyme conformation fluctuations.

[1] « Ribozymes », W. Scott, Curr. Op. Struct. Biol., 2007, 17, 280-286
[2] « Metal ions in ribozyme folding and catalysis », R. Hanna, J.A. Doudna, Curr. Op. Chem. Biol.,2000, 4, 166-170
[3] « Extraordinary rates of transition metal ion-mediated ribozyme catalysis. » M. Roychowdhury-Saha, D.H. Burke, RNA, 2006, 12, 1846-1852
[4] « Two active site divalent ions in the crystal structure of the Hammerhead ribozyme bound to a transition state analogue », A. Mir, B.L. Golden, Biochemistry, 2016, 55, 633-636
Interdisciplinary aspect of the project: This project uses physical theories and computational tools to understand at the molecular level the behavior of biological systems. It thus requires having a broad interest both in simulation, chemistry and biological systems, if possible with a basic knowledge in statistical physics.