Helium Nanodroplet Forcefield for Advancing Single-Molecule Serial Electron Diffraction Imaging.

Single-molecule Serial Electron Diffraction (SS-EDI) is a promising methodology to determine biomolecular structures, which employs Helium Nanodroplets (HNDs) as the sample delivery system. Until now, structural determination methods have used liquid Helium only as a coolant, but SS-EDI offers a novel application for HNDs as an embedding matrix to isolate single molecules in an ultracold and weakly interacting fluid environment with minimal scattering. SS-EDI is still under active development and to advance it, researchers require an understanding of the interactions within HNDs at the nanoscale level. To support ongoing experimental efforts, we present a Molecular Dynamics (MD) forcefield for HNDs at 0.38 K, enabling direct calculation of electron diffraction patterns from atomic configurations. Our forcefield combines a Morse potential for van der Waals interactions with a Drude oscillator to capture polarization effects induced by charged dopants, and its parameters were validated against four key quantities of interest: bulk density, an upper bound for viscosity, droplet stability, and the radial profile of the average electron diffraction signal. During validation, we identified instabilities associated with polarizable model at ultralow temperatures, and mitigate them by reducing the effective polarizability, introducing an "ultracold" Drude particle, and employing canonical ensembles. Finally, we applied the forcefield to simulate HNDs doped with a tri-atom Argon ion, and the changes in electron diffraction profiles were compared with experimental measurements of HNDs of similar size. Despite significant statistical fluctuations in both simulation and experiment, the simulations reproduce the key peak positions observed experimentally, demonstrating qualitative agreement between them. These results establish MD simulations as a valuable tool to advance the application of liquid Helium as a new embedding matrix for structural determination.