Molecular interpretation of single-molecule force spectroscopy experiments with computational approaches

Single molecule force-spectroscopy techniques have granted access to unprecedented molecular-scale details about biochemical and biological mechanisms. However, the interpretation of the experimental data is often challenging and it benefits from the perspective brought by computational approaches. In many cases, these simulations (all-atom steered MD simulations in particular) are key to provide molecular details about the associated mechanisms, to help test different hypotheses and to predict experimental results. We will review here some of our recent efforts directed towards the molecular interpretation of single-molecule force spectroscopy experiments on proteins and protein-related systems, often in close collaboration with experimental groups. These results will be discussed in the broader contexts of the field, highlighting the recent achievements and the ongoing challenges for computational biophysicists and biochemists. In particular, we will focus on the input gained from molecular simulations approaches to rationalize the origins for the unfolded protein elasticity and the protein conformational behavior under force, to understand how force denaturation differs from chemical, thermal or shear unfolding, and to unravel the molecular details of unfolding events for a variety of systems. We will also discuss the use of models based on Langevin dynamics on a 1-D free-energy surface to understand the effect of protein segmentation on the work exerted by a force, or, at the other end of the spectrum of computational techniques, how quantum calculations can help to understand the reactivity of disulfide bridges exposed under force.