Simulating Chalcogen Bonding Using Molecular Mechanics: A Pseudoatom Approach to Model Ebselen.

The organoselenium compound ebselen has recently been investigated as a treatment for COVID-19, however<br>efforts to model ebselen in silico have been hampered by the lack of a efficient and accurate method to assess<br>its binding to biological macromolecules. We present here a Generalized Amber Force Field modification which<br>incorporates classical parameters for the selenium atom in ebselen, as well as a positively charged pseudoatom to<br>simulate the sigma?-hole, a quantum mechanical phenomenon that dominates the chemistry of ebselen. Our approach<br>is justified using an energy decomposition analysis of a number DFT optimised structures, which shows that the<br>?sigma-hole interaction is primarily electrostatic in origin. Finally, our model is verified by conducting MD simulations<br>on a number of simple complexes, as well the clinically relevant SOD1, which is known to bind to ebselen.