@article {2018|2137, title = {Conformational entropy of a single peptide controlled under force governs protease recognition and catalysis}, journal = {Proc Natl Acad Sci U S A}, volume = {115}, year = {2018}, month = {11}, pages = {11525-11530}, abstract = {

An immense repertoire of protein chemical modifications catalyzed by enzymes is available as proteomics data. Quantifying the impact of the conformational dynamics of the modified peptide remains challenging to understand the decisive kinetics and amino acid sequence specificity of these enzymatic reactions in vivo, because the target peptide must be disordered to accommodate the specific enzyme-binding site. Here, we were able to control the conformation of a single-molecule peptide chain by applying mechanical force to activate and monitor its specific cleavage by a model protease. We found that the conformational entropy impacts the reaction in two distinct ways. First, the flexibility and accessibility of the substrate peptide greatly increase upon mechanical unfolding. Second, the conformational sampling of the disordered peptide drives the specific recognition, revealing force-dependent reaction kinetics. These results support a mechanism of peptide recognition based on conformational selection from an ensemble that we were able to quantify with a torsional free-energy model. Our approach can be used to predict how entropy affects site-specific modifications of proteins and prompts conformational and mechanical selectivity.

}, keywords = {enzymology, mechanics, proteases, single molecule, torsional free energy}, doi = {10.1073/pnas.1803872115}, author = {Guerin, Marcelo E and Guillaume Stirnemann and Giganti, David} } @article {2017|2025, title = {Critical structural fluctuations of proteins upon thermal unfolding challenge the Lindemann criterion}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {Aug}, pages = {9361-9366}, abstract = {

Internal subnanosecond timescale motions are key for the function of proteins, and are coupled to the surrounding solvent environment. These fast fluctuations guide protein conformational changes, yet their role for protein stability, and for unfolding, remains elusive. Here, in analogy with the Lindemann criterion for the melting of solids, we demonstrate a common scaling of structural fluctuations of lysozyme protein embedded in different environments as the thermal unfolding transition is approached. By combining elastic incoherent neutron scattering and advanced molecular simulations, we show that, although different solvents modify the protein melting temperature, a unique dynamical regime is attained in proximity of thermal unfolding in all solvents that we tested. This solvation shell-independent dynamical regime arises from an equivalent sampling of the energy landscape at the respective melting temperatures. Thus, we propose that a threshold for the conformational entropy provided by structural fluctuations of proteins exists, beyond which thermal unfolding is triggered.

}, keywords = {cell thermal stability, Lindemann criterion, Molecular Dynamics Simulation, neutron scattering, protein dynamics}, doi = {10.1073/pnas.1707357114}, author = {Katava, Marina and Guillaume Stirnemann and Zanatta, Marco and Capaccioli, Simone and Pachetti, Maria and Ngai, K L and Sterpone, Fabio and Paciaroni, Alessandro} } @article {2012|1676, title = {Communication: On the origin of the non-Arrhenius behavior in water reorientation dynamics}, journal = {J. Chem. Phys.}, volume = {137}, year = {2012}, abstract = {

We combine molecular dynamics simulations and analytic modeling to determine the origin of the non-Arrhenius temperature dependence of liquid water{\textquoteright}s reorientation and hydrogen-bond dynamics between 235 K and 350 K. We present a quantitative model connecting hydrogen-bond exchange dynamics to local structural fluctuations, measured by the asphericity of Voronoi cells associated with each water molecule. For a fixed local structure the regular Arrhenius behavior is recovered, and the global anomalous temperature dependence is demonstrated to essentially result from a continuous shift in the unimodal structure distribution upon cooling. The non-Arrhenius behavior can thus be explained without invoking an equilibrium between distinct structures. In addition, the large width of the homogeneous structural distribution is shown to cause a growing dynamical heterogeneity and a non-exponential relaxation at low temperature.

}, issn = {00219606}, author = {Guillaume Stirnemann and Laage, Damien} }