Collective residue interactions in trimer complexes of SARS-CoV-2 spike proteins analyzed by fragment molecular orbital method

In large biomolecular systems such as protein complexes, there are huge numbers of combinations of inter-residue interactions whose comprehensive analyses are often beyond the intuitive processing by researchers. Here we propose a computational method to allow for a systematic analysis of these interactions based on the fragment molecular orbital calculations, in which the inter-fragment interaction energies are comprehensively processed by the singular value decomposition. For a trimer complex of SARS-CoV-2 spike protein, three-body interactions among residues belonging to three chains are analyzed to elicit a small number of essential interaction modes or networks crucial for the structural stability of the complex.

Intermolecular interaction among Remdesivir, RNA and RNA-dependent RNA polymerase of SARS-CoV-2 analyzed by fragment molecular orbital calculation.

COVID-19, a disease caused by a new strain of coronavirus (SARS-CoV-2) originating from Wuhan, China, has now spread around the world, triggering a global pandemic, leaving the public eagerly awaiting the development of a specific medicine and vaccine. In response, aggressive efforts are underway around the world to overcome COVID-19. In this study, referencing the data published on the Protein Data Bank (PDB ID: 7BV2) on April 22, we conducted a detailed analysis of the interaction between the complex structures of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and Remdesivir, an antiviral drug, from the quantum chemical perspective based on the fragment molecular orbital (FMO) method. In addition to the hydrogen bonding and intra-strand stacking between complementary strands as seen in normal base pairs, Remdesivir bound to the terminus of an primer-RNA strand was further stabilized by diagonal π-π stacking with the -1A' base of the complementary strand and an additional hydrogen bond with an intra-strand base, due to the effect of chemically modified functional group. Moreover, stable OH/π interaction is also formed with Thr687 of the RdRp. We quantitatively revealed the exhaustive interaction within the complex among Remdesivir, template-primer-RNA, RdRp and co-factors, and published the results in the FMODB database.