Systemic Effects of Missense Mutations on SARS-CoV-2 Spike Glycoprotein Stability and Receptor Binding Affinity

Abstract

The spike (S) glycoprotein of SARS-CoV-2 is responsible for the binding to the permissive cells.The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18,354 mutations in S protein were analyzed and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3,705 mutations in SARS-CoV-2 RBD and 11,324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD-ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.Coronaviruses are a large family of enveloped RNA viruses typically transmitted from animals to animals. These viruses are usually found in bats, birds, and mammals (1), but seven coronavirus members are found to infect humans. The paradigm shift in the mode of transmission of three pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), has resulted in recent outbreaks. The SARS-CoV epidemic began in Shunde, Guangdong, China, in November 2002. It ended in 2003 with more than 8000 cases in over 28 countries and ~800 deaths. The presence of a SARS-CoV-like coronavirus in bats indicated that the natural reservoir of SARS-CoV is horseshoe bat (2, 3). The MERS-CoV epidemic began in Saudi-Arabia in June 2012, and the transmission of MERS-CoV crossed the Arab peninsula to nearby countries. Scientists revealed that the Arabian camel (dromedaries) is the reservoir host to MERS-CoV, and they also spread the virus to humans. As of January 2020, the World Health Organization (WHO) reported 2,519 MERS-CoV cases in 27 countries and ~866 deaths. Although both SARS-CoV and MERS-CoV were transmitted from animals to humans, human to human transmission was found plausible (2). The most recent outbreak of Coronavirus Disease 2019 (COVID-19) is caused by a novel coronavirus, SARS-CoV-2. The virus is closely related to the SARS-like CoV, RaTG13 virus which is found in bats (4). SARS-CoV-2 is so far the most pathogenic coronavirus. As of May 23, 2020, WHO reported over 5 million confirmed cases of COVID-19 in 216 countries, resulting in > 331,000...

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