Exploring Cucurbituril-Fentanyl Binding (and Beyond) with Parallel Biasing Methods

The physics underlying drug delivery, molecular separation, and detection of harmful agents relies in many cases on microscopic binding events. There is a critical need for information about these processes, in particular from molecular simulations which can be used to pre-screen molecules and materials. Binding events can be simple, such as gas molecules adsorbing onto surfaces, or complex, such as protein-ligand interactions. Here, we discuss new techniques for computing the binding free energy of small organic molecules to cucurbituril (CB) macrocycles (specifically, cucurbit[7]uril with fentanyl) as both a test case of intermediate complexity, and one of great potential application in sensing and remediation platforms. The system exhibits multiple potential binding conformations, rendering computational study of CB–fentanyl binding difficult with standard methods. Parallel biasing metadynamics is used to enhance sampling in this system along multiple important structural and dynamic degrees of freedom, without restricting the movement between bound states. We compare our results to experiment and discuss the general applicability of the parallel biasing scheme to alternate systems.