Let's Stalk about Membranes: Committor-Based Enhanced Sampling of Stalk Formation

Membrane fusion is essential for cellular communication and function, and understanding how two lipid bilayers merge is the key to informing therapeutic strategies. Functionalized nanoparticles have recently emerged as synthetic fusogens, but the molecular mechanisms driving this process remain unclear, partly because fusion involves transitions over high free-energy barriers, which are difficult to capture in molecular simulations. While enhanced sampling methods can address this problem, they also rely on the definition of collective variables, which are especially hard to define for fusion as it arises from the collective rearrangement of many molecules and cannot be easily reduced to a simple intuitive coordinate. Here, we study stalk formation, the first step of fusion, mediated by an amphiphilic gold nanoparticle, by employing an enhanced sampling strategy based on the committor function, machine-learned through a self-consistent procedure. This method requires minimal prior knowledge of the system and leverages the learned committor function as an effective collective variable, enabling the uniform sampling of the entire pathway. From the resulting reactive trajectories and extensive transition region sampling, we obtained converged free-energy estimates and mechanistic insight into stalk formation.