Abiotic ribonucleic-acid synthesis - ERC StG ABIOS
Starting January 2018, I am leading a project focussing of some critical steps of abiotic RNA synthesis, which has key implications for the origins of life on Earth. Indeed, RNA is currently seen as a good candidate for the first biomolecule as it is capable of both genetic information storage and catalysis, including its self-replication. More details can be found in the dedicated section.
Mechanical Forces on Proteins
My current research also deals with various aspects of protein behavior undor force.
Single molecule force-spectroscopy techniques represent a whole new and exciting field providing unprecedented details about biochemical and biological mechanisms at a molecular scale. However, interpretation of the experimental data is often challenging and benefits from the perspective brought by steered molecular dynamics (SMD) simulations. In many cases, SMD simulations are key to provide molecular details about the associated mechanisms, to help testing different hypotheses and to predict experimental results.
Some of my recent research has been devoted to the comparison between thermal and mechanical stability of proteins, with a special emphasis on thermophilic organisms. In particular, we have implemented an enhanced-sampling algorithm which allows us to explore the proteins' free-energy landscape over a wide range of temperatures, and we have used constant-force steered MD to investigate the effect of mechanical force. Our results (1) suggest that thermal stability does not guarantee a mechanical one and that the associated unfolding mechanisms, of which our simulations provide extensive details, are very different. We also aim at identifying the weak-points of the protein mechanical stability and how more stable mutants can be designed.
I am involved in an active collaboration with the group of Pr. Sergi Garcia-Manyes at King's College (London), with which I work in tandem to provide a better molecular understanding of some facinating expererimental results. In particular, we have been focusing on e.g. the mechanical unfolding of copper-binding proteins (2). Simulations and experiments show evidence of a novel kinetic partitioning scenario whereby the protein can stochastically unfold through two distinct main unfolding transition states placed at the N- and C- termini that precisely dictate the unfolding direction, because of the unique ability of the metal to allow identification of intermediate states along the unfolding pathway. More recent work has addressed the fine tuning of protein nanomechanics with the chemical reactivity of its disulfide bonds (3), or the peculiar force-dependence of the binding of a protein co-chaperone DnaJ to its substrate.
- G. Stirnemann and F. Sterpone, Mechanics of Protein Adaptation to High Temperatu-res, J. Phys. Chem. Lett 8, 5884-90 (2017)
- A. Beedle, A. Lezamiz, G. Stirnemann and S. Garcia-Manyes, The Mechanochemistry of Copper Reports on the Directionality of Unfolding in Model Cupredoxin Proteins, Nat. Commun. 6, 7894 (2015)
- A. Beedle, M. Mora, S. Lynham, G. Stirnemann and S. Garcia-Manyes, Tailoring Protein Nanomechanics with Chemical Reactivity , Nat. Commun. 8, 15658 (2017)
H-Bond Dynamics in Aqueous Systems
In continuation of my PhD work with Damien Laage at Ecole Normale Superieure in Paris, I keep a strong interest for water reorientation dynamics in various types of aqueous solutions. We have recently been revisiting our earlier classical MD results about water hydrogen-bond dynamics next to a amphiphilic molecule using ab-initio MD (1), and found that our conclusions and model remained unaffected as compared to fully-classical approaches. In particular, we had shown that water molecules are only moderately slowed by hydrophobic groups because of an excluded volume effect (2) and that hydrophilic groups may have a much more pronounced effect on the water dynamics (with a combination of hydrogen-bond strength and excluded volume effects), developing a unique framework to subsequently understand water dynamics in more complex, biological systems (3).
At extended hydrophobic interfaces, water molecules tend to sacrifice some of their hydrogen-bonds, giving rise to dangling OH groups pointing toward the interface. In collaboration with the experimental group of John McGuire, we have been examining the reorientation dynamics of this OH population (2), and found that they were slightly more retarded at organic hydrophobic interface as compared to the air/liquid water interface, because of slightly more favorable interactions that we characterized and quantified using our simulations.
- G. Stirnemann, E. Duboué-Dijon and D. Laage Ab Initio Simulations of Water Dynamics in Aqueous TMAO Solutions: Temperature and Concentration Effects , J. Phys. Chem. B 121, 11189–97 (2017)
- D. Laage, G. Stirnemann and J. T. Hynes. Why Water Reorientation Slows without Iceberg Formation around Hydrophobic Solutes, J. Phys. Chem. B 113, 2428-35 (2009)
- F. Sterpone, G. Stirnemann and D. Laage. Communication: Magnitude and Molecular Origin of Water Slowdown Next to a Protein, J. Am. Chem. Soc. 134, 4116-9 (2012)
- S. Xiao, F. Figge, G. Stirnemann, D. Laage, and J. A. McGuire Orientational Dynamics of Water at an Extended Hydrophobic Interface, J. Am. Chem. Soc. 138, 5551–60 (2016)