Molecular Insights into the Binding Behavior of Imidazolium Ionic Liquids to the Receptor Binding Domain of the SARS-CoV-2 Spike Protein

Abstract

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is considered as a key target for the design and development of COVID-19 drugs and inhibitors. Due to their unique structure and properties, ionic liquids (ILs) have many special interactions with proteins, showing great potential in biomedicine. Nevertheless, few research studies have been carried out on ILs and the spike RBD protein. Here, we explore the interaction of ILs and the RBD protein through large-scale molecular dynamics simulations (4 μs in total). It was found that IL cations with long alkyl chain lengths (nchain) could spontaneously bind to the cavity region of the RBD protein. The longer the alkyl chain is, the stabler the cations bind to the protein. The binding free energy (ΔG) had the same trend, peaking at nchain = 12 with -101.19 kJ/mol. The cationic chain lengths and their fit to the pocket are decisive factors that influence the binding strength of cations and proteins. The cationic imidazole ring has a high contact frequency with phenylalanine and tryptophan, and the hydrophobic residues phenylalanine, valine, leucine, and isoleucine are the most interacting residues with side chains of cations. Meanwhile, through analysis of the interaction energy, the hydrophobic and π-πinteractions are the main contributors to the high affinity between cations and the RBD protein. In addition, the long-chain ILs would also act on the protein through clustering. These studies not only provide insights into the molecular interaction between ILs and the RBD of SARS-CoV-2 but also contribute to the rational design of IL-based drugs, drug carriers, and selective inhibitors as a therapeutic for SARS-CoV-2.