Interaction analyses of SARS-CoV-2 spike protein based on fragment molecular orbital calculations

Abstract

At the stage of SARS-CoV-2 infection in human cells, the spike protein consisting of three chains, A, B, and C, with a total of 3300 residues plays a key role, and thus its structural properties and the binding nature of receptor proteins to host human cells or neutralizing antibodies has attracted considerable interest. Here, we report on interaction analyses of the spike protein in both closed (PDB-ID: 6VXX) and open (6VYB) structures, based on large-scale fragment molecular orbital (FMO) calculations at the level of up to the fourth-order Møller-Plesset perturbation with singles, doubles, and quadruples (MP4(SDQ)). Inter-chain interaction energies were evaluated for both structures, and a mutual comparison indicated considerable losses of stabilization energies in the open structure, especially in the receptor binding domain (RBD) of chain-B. The role of charged residues in inter-chain interactions was illuminated as well. By two separate calculations for the RBD complexes with angiotensin-converting enzyme 2 (ACE2) (6M0J) and B38 Fab antibody (7BZ5), it was found that the binding with ACE2 or antibody partially compensated for this stabilization loss of RBD.

Fig. 1. Graphical representations of calculated protein structures. Red, green, and blue indicate chains A, B, and C, respectively, for the closed (a), 6VXX and open (b), 6VYB spike protein. The darker colors identify RBDs in the chains. For the RBD–ACE2 complex (c) 6M0J, RBD and ACE2 are colored green and orange, respectively. Heavy and light chains are colored light-blue and magenta, respectively, for the RBD–B38 Fab complex (d), 7BZ5.

Fig. 2. Inter-chain IFIE sums (a) for the closed structure (6VXX) and (b) for the open structure (6VYB). Refer also to the numerical values in Tables S1 and S2.

Fig. 3. Inter-chain IFIE sums from RBD for (a) the closed structure (6VXX) and (b) the open structure (6VYB). Refer also to Tables S4 and S5.

Fig. 4. Positions of important residues with differences in IFIEs (more than 150 kcal mol⁻¹) between the closed (6VXX) and open (6VYB) structures.

Fig. 5. IFIE sums between spike RBD and ACE2 (6M0J) and spike RBD and B38 Fab (7BZ5). Refer also to Tables S8 and S9.