The binding process of angiotensin-converting enzyme 2 (ACE2) to the receptor-binding domain (RBD) of the severe acute respiratory syndrome-like coronavirus 2 spike protein was investigated using molecular dynamics simulation and the three-dimensional reference interaction-site model theory. The results suggested that the protein-binding process consists of a protein–protein approaching step, followed by a local structural rearrangement step. In the approaching step, the interprotein interaction energy decreased as the proteins approached each other, whereas the solvation free energy increased. As the proteins approached, the glycan of ACE2 first established a hydrogen bond with the RBD. Thereafter, the number of interprotein hydrogen bonds increased rapidly. The solvation free energy increased because of the desolvation of the protein as it approached its partner. The spatial distribution function of the solvent revealed the presence of hydrogen bonds bridged by water molecules on the RBD–ACE2 interface. Finally, principal component analysis revealed that ACE2 showed a pronounced conformational change, whereas there was no significant change in RBD.

A combined method of the Dirac-Hartree-Fock (DHF) method and the reference interaction-site model (RISM) theory is reported; this is the initial implementation of the coupling of the four-component relativistic electronic structure theory and an integral equation theory of molecular liquids. In the method, the DHF and RISM equations are solved self-consistently, and therefore the electronic structure of the solute, including relativistic effects, and the solvation structure are determined simultaneously. The formulation is constructed based on the variational principle with respect to the Helmholtz energy, and analytic free energy gradients are also derived using the variational property. The method is applied to the iodine ion (I À ), methyl iodide (CH 3 I), and hydrogen chalcogenide (H 2 X, where X = O-Po) in aqueous solutions, and the electronic structures of the solutes, as well as the solvation free energies and their component analysis, solvent distributions, and solute-solvent interactions, are discussed.

The reference interaction site model self-consistent field (RISM-SCF) method is a combined method of the electronic structure theory of molecules and the integral equation theory of molecular liquids. The RISM-SCF method based on the Dirac-Hartree-Fock wave function, recently proposed, is applied to a chemical reaction, specifically, a Menshutkin reaction in aqueous solution. The Helmholtz energy profile along the reaction coordinate is calculated and the characteristics of the reaction are discussed based on energy component analysis.