A recent study published in the journal Frontiers in Molecular Biosciences applied computational approaches to study the binding mechanisms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV spike (S) proteins to the human angiotensin-converting enzyme 2 (ACE2) receptor.

Study: Spike proteins of SARS-COV and SARS-COV-2 utilize different mechanisms to bind with human ACE2. Image Credit: Kateryna Kon / Shutterstock.com

Rationale of the study

The coronavirus disease 2019 (COVID-19), which is caused by infection with SARS-CoV-2, has caused over 6.6 million deaths since its initial discovery at the end of 2019.

In addition to SARS-CoV-2, other viruses that belong to the Coronaviridae family include the Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, both of which led to epidemics in 2012 and 2003, respectively. These coronaviruses consist of four primary structural proteins, of which include the S, envelope (E), membrane (M), and nucleocapsid (N) proteins.

Although the structure of the SARS-CoV-2 and SARS-CoV S proteins are similar, the binding affinity of the SARS-CoV-2 S protein to the ACE2 receptor is much higher as compared to SARS-CoV, which may account for its increased transmissibility.

Study findings

Upon comparison of the SARS-CoV and SARS-CoV-2 S proteins, mutations were widely distributed throughout the surface of the SARS-CoV-2 S protein. More specifically, mutations present within the receptor binding domain (RBD) region of the S protein that was adjacent to the interface that directly interacts with the ACE2 receptor were observed. These findings indicate that the mechanisms by which the SARS-CoV and SARS-CoV-2 S proteins bind to and interact with the ACE2 receptor are extremely different.

The gross structure of both the SARS-CoV and SARS-CoV-2 S protein RBDs were found to be very similar. However, certain differences in several loops were identified and can be attributed to the high loop flexibility and differences in the amino acids that comprise these viral proteins.

Investigation into the electrostatic surface differences between the two viral proteins indicated that the ACE2 binding interface is dominantly negative, whereas that of the S protein RBD is positive. Furthermore, the SARS-CoV-2 S protein RBD exhibits a greater degree of attraction to the ACE2 receptor as compared to the SARS-CoV RBD. This high level of attraction may account for the increased formation of non-covalent bonds like salt bridges and hydrogen bonds between the SARS-CoV-2 RBD and ACE2. 

A cluster of residues, aside from salt-bridge residues, is used by the SARS-CoV-2 during interaction with ACE2 that are also stronger as compared to the individual salt bridges.

Both SARS-CoV-2 and SARS-CoV complex structures exhibited similar in the field lines. Field lines connecting ACE2 and both S proteins had high densities surrounding the surfaces, thus indicating strong attractive forces between the ACE2 protein and the S protein RBD of both viruses.

Nevertheless, various differences in the interface areas were observed. For example, electric field line-associated residues were unevenly distributed between the viruses, as the salt bridge residues were found to be distributed on opposite sides of the SARS-CoV and SARS-CoV-2 RBDs.

SARS-CoV-2 was found to exhibit a larger and more connected distribution of hydrogen bonds, as well as a more concentrated yet separated distribution of salt bridges. Furthermore, SARS-CoV-2 was found to consist of five major special regions, whereas SARS-CoV contained only two.

A comparison of the electrostatic forces of both the SARS-CoV-2 and SARS-CoV RBDs revealed that the SARS-CoV-2 RBD exhibits a greater net force as compared to that of SARS-CoV-2 alone. This may be attributed to differences in the charge distributions between these two binding domains. Despite a weaker attractive force, the increased flexibility of the SARS-CoV-2 RBD likely allows for it to open and subsequently bind to ACE2 with greater ease.

Four salt bridge residues labeled for the SARS-CoV RBD were labeled, of which included LYS465, LYS390, ASP468, and ARG426. Among these, ARG426 provides a greater attractive force to ACE2, whereas LYS465 is a more repulsive force against ACE2.

Conclusions

Despite the structural similarities between the SARS-CoV and SARS-CoV-2 S proteins, the current study reported vast differences in how these viral proteins bind to and interact with the human ACE2 receptor. One of the key observations in the current study is the attractive forces that exist between the SARS-CoV-2 RBD and ACE2 as a result of the negative charge of the ACE2 binding surface as compared to the positively charged SARS-CoV-2 RBD.

As the number of infections caused by SARS-CoV-2 continues to rise throughout the world, it is imperative to better understand how this virus infects humans. Thus, the current study findings can be used to design new drugs and treatments capable of interfering with how SARS-CoV-2 S protein binds to ACE2 to cause infection.