Research Interests

Mechanical Forces on Proteins

My current research mainly deals with various aspects of protein behavior undor force.

I started working on this topic as a postdoc in the Berne group in the chemistry department of Columbia University, in strong collaboration with the experimental group of Prof. Julio Fernandez in the biology department. 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.

In particular, we have shown that while proteins under force in the experiments sample the same PMF as in the simulations, motions on the free-energy surface are solely limited by the drag on the objects they are necessarily tethered to (1). Motions of "free" proteins as studied in simulations or in other experimental techniques (e.g. FRET) are occuring on a much faster timescale; force does not dramatically affect internal diffusion of the protein, only its PMF. These results are of crucial importance for interpretation of experimental rates and free-energy barriers, as well as for biological systems where proteins under tension are often tethered to larger macromolecular objects.

On another perspective, we offered a molecular picture of classic descriptions of proteins under force (2), such as the worm-like chain model from polymer physics. We addressed questions such as: what are the protein degrees of freedom affected by force? What is responsible for the protein flexibility? What is the persistence length due to? We have also offered a detailed comparison of force- and chemical/thermal-denaturation with colleagues at the IBM TJ Watson Research Center (3).

Since I joined the Theoretical Biochemistry Lab of IBPC in Paris, first as a postdoc in the group of Dr. Fabio Sterpone, and now as an independent CNRS permanent researcher, I have been focusing on 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 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.

More recent research in collaboration with the group of  Pr. Sergi Garcia-Manyes at King's College (London) has been focusing on the mechanical unfolding of copper-binding proteins. 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 (4).


  1. R. Berkovich, R. I. Hermans, I. Popa, G. Stirnemann, S. Garcia-Manyes, B. J. Berne and J. M. Fernandez. Rate Limit of Protein Elastic Response is Tether Dependent, Proc. Natl. Acad. Sci. USA 109, 14416-21 (2012)
  2. G. Stirnemann, D. Giganti, J. M. Fernandez and B. J. Berne. Elasticity, Structure and Relaxation of Extended Proteins under Force, Proc. Natl. Acad. Sci. USA 110, 3847-52 (2013)
  3. G. Stirnemann, S-g Kang, R. Zhou and B. J. Berne. How Force Unfolding Differs from Chemical Denaturation, Proc. Natl. Acad. Sci. USA 111, 3413-8 (2014)
  4. A. Beedle, A. Lezamiz, G. Stirnemann and S. Garcia-Manyes, The Mechanochemistry of Copper Reports on the Directionality of Unfolding in Model Cupredoxin Proteins, accepted for publication, Nature Comm. XX, (2015)


H-Bond Dynamics in Aqueous Systems 

During my PhD under the supervision of Damien Laage at Ecole Normale Superieure in Paris, I have investigated various aspects of water reorientation dynamics using simulation and analytic tools, in strong connection with experiments. We mainly focussed on the molecular mechanism of water reorientation, which involves large angular jumps due to the exchange of hydrogen-bond acceptors. Within this framework, we have brought significant new insights on reorientation dynamics in aqueous solutions of ions (1), the temperature-dependence (2) and interpretation of recent nonlinear spectroscopy measurements in the bulk case (3). We have also rationalized the effect of various solutes on water dynamics, including hydrophobes, amphiphiles, and extended surfaces. In particular, we have shown that water molecules are only moderately slowed by hydrophobic groups (4) and that hydrophilic groups may have a much more pronounced effect on the water dynamics, developing a unique framework to subsequently understand water dynamics in more complex, biological systems (5).

Current efforts include ab-initio MD simulations of aqueous solutions of amphiphilic solutes in order to confirm the results previously obtained with classical MD. 

  1. G. Stirnemann, E. Wernersson, P. Jungwirth and D. Laage. Mechanisms of Acceleration and Retardation of Water Dynamics by Ions, J. Am. Chem. Soc. 135, 11824-31 (2013)
  2. G. Stirnemann and D. Laage. Communication: On the Origin of the Non-Arrhenius Behavior in Water Reorientation Dynamics, J. Chem. Phys. 137, 031101 (2012)
  3. G. Stirnemann and D. Laage, Direct Evidence of Angular Jumps During Water Reorientation Through Two-Dimensional Infrared Anisotropy, J. Phys. Chem. Lett. 1, 1511-5 (2010)
  4. 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)
  5. 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)