Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies

Abstract

The recent severe acute respiratory syndrome, known as Coronavirus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare a state of emergency over the new coronavirus SARS-CoV-2 pandemic. While several countries have chosen the almost complete lock-down for slowing down SARS-CoV-2 spread, the scientific community is called to respond to the devastating outbreak by identifying new tools for diagnosis and treatment of the dangerous COVID-19. With this aim, we performed an in silico comparative modeling analysis, which allows gaining new insights into the main conformational changes occurring in the SARS-CoV-2 spike protein, at the level of the receptor-binding domain (RBD), along interactions with human cells angiotensin-converting enzyme 2 (ACE2) receptor, that favor human cell invasion. Furthermore, our analysis provides (1) an ideal pipeline to identify already characterized antibodies that might target SARS-CoV-2 spike RBD, aiming to prevent interactions with the human ACE2, and (2) instructions for building new possible neutralizing antibodies, according to chemical/physical space restraints and complementary determining regions (CDR) mutagenesis of the identified existing antibodies. The proposed antibodies show in silico high affinity for SARS-CoV-2 spike RBD and can be used as reference antibodies also for building new high-affinity antibodies against present and future coronaviruses able to invade human cells through interactions of their spike proteins with the human ACE2. More in general, our analysis provides indications for the setup of the right biological molecular context for investigating spike RBD-ACE2 interactions for the development of new vaccines, diagnostic kits, and other treatments based on the targeting of SARS-CoV-2 spike protein.

Immunoinformatic Analysis of SARS-CoV-2 Nucleocapsid Protein and Identification of COVID-19 Vaccine Targets

“…The S protein comprises two subunits: S1 and S2. The S1 subunit consists of an amino-terminal domain and a receptor-binding domain (RBD) (5,6). The RBD binds to ACE2 as its host cell target receptor, which allows virus entry (5,7).…”

Plausible Blockers of Spike RBD in SARS-CoV2 – Molecular Design and Underlying Interaction Dynamics from High-Level Structural Descriptors<b> </b>

“…Hence, yet being attracted to ACE2 faster than that in CoV, the RBDSpike in CoV-2 would also get released from the receptor faster as the unfavorable electrostatic interactions would act against a stable binding. The lower stability in the co-complex in CoV-2 relative to that in CoV can also be cross-validated by comparing the 'dG_separated' values for both, computed by structure driven thermodynamic calculations using Rosetta [23]. Interestingly, in spite of the sub-optimal EC, the increase in Sc in CoV-2 relative to CoV results in a right-shift along the horizontal axis of the corresponding resultant point (CoV-2) in CPdock making the point map to the near optimal zone (~ 'less probable' region).…”

“…This implies a more complex mechanism behind the molecular access of SARS-CoV-2 into the host cell [21]. Moreover, the S1 trimer continuously switches between a 'lying down' and a 'standing up' position onto the S2 subunits [15,16,23]. When it is at a 'lying down' position, the S1-RBD remains hidden and unexposed enabling the SARS-CoV-2 to escape the host immune surveillance [16].…”

Docking and QSAR of Aminothioureas at the SARS-CoV-2 S-Protein–Human ACE2 Receptor Interface

“…One of the targets of both types of studies is the interface between the virus S-protein and the ACE2 receptor, focused on complex stabilizers and protein-protein binding inhibitors. Recent studies in this area include experimental [3,4] and theoretical [5][6][7][8] structural analyses, as well as mutagenic studies [9]. Advances from all these studies have been summarized [10].…”

“…By combining virtual high-throughput screening with ensemble docking of over 9000 compounds from the SWEETLAND library [20] and by using SARS-CoV-2 S-protein (NCBI: YP_009724390.1) and human ACE2 receptor (PDB: 2AJF) as templates to generate the SARS-CoV-2 S-protein-ACE2 receptor complex model, around 80 compounds already in clinical use that should exhibit anti-coronavirus activity have been identified. The S-protein-ACE2 receptor interface is continuing to be a subject of vigorous structural [3,4] and mutagenic [9] experimental studies, as well as of theoretical assessments [5][6][7]21]. The implications of these studies for therapy have been summarized recently [10].…”