Computational Assessment of Receptor-Ligand Unbinding Under Applied Force

Abstract

Receptor-ligand interactions are ubiquitous and are crucial to physiological functions, such as immune response, cell growth, and cell proliferation. Computational methods such as Molecular Dynamics with enhanced sampling facilitate the study of the thermodynamics and kinetics profiles of receptor-ligand unbinding. Numerous studies have used MD and Infrequent Metadynamics to obtain a molecular description of the unbinding process. As a result, a number of molecular mechanisms giving rise to ligand unbinding, and unbinding rates have been reported. However, the role of mechanical forces has not been included in these types of calculations. Unbinding rates are thought to have complex dependencies on pulling forces but the effects of forces have not been predicted by simulations. A prototypical cavity-ligand model was used to explore the effects of pulling forces in the thermodynamic and kinetics profiles of ligand unbinding. We first demonstrate the effects of mechanical forces on unbinding rates in four variants of this model, and later we perform the same type of calculations using a fully atomistic system, the Streptavidin-biotin complex. We demonstrate that in the cavity-ligand model, the forces lower the free energy barriers to unbinding which in turn increase unbinding rates exponentially with applied force; hence this behavior can be described as following Bell’s law. However, in the SA-b complex the unbinding rates exhibit a more complex dependence on the pulling forces due to the existence of meta-stable intermediates.