Simulating chalcogen bonding using molecular mechanics: a pseudoatom approach to model ebselen

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