The Physics and Chemistry of Viral Protein Interactions for SARS-CoV-2 

“..the things that are seen in the biological world are the results of the behavior of physical and chemical phenomena, with no extra something.” 
R. Feynman, Messenger Lectures, Cornell, 1964 
The SARS-CoV-2 virus responsible for the COVID-19 pandemic is fully subject to the laws of physics and chemistry. Many key worldwide pandemic trends that have manifested can be traced to protein-protein interactions in a simple mechanistic manner that can be readily described in terms of well-known concepts of physics and chemistry, specifically the Coulomb attraction between opposite charges, and hydrogen bonds between proteins. In this presentation I will focus on four protein-protein interactions that have played the biggest role in pandemic outcomes. First, I will describe how a single mutation in the SARS-CoV-2 spike protein removed a Coulomb interaction that allowed for more frequent opening of the binding region to the human receptor protein ACE2. Second, I will explain considerable evidence shows that both SARS-CoV-1 and SARS-CoV-2 have nearly optimal binding to the ACE2 protein, which means it is difficult to find mutations that increase the binding strength to allow for more frequent cell entry, but easy to reduce it. This is important for the third binding story, of antibodies to the spike protein: omicron and its descendants are filled with mutations that allowed a jump from the human immune system, but weaken the cell binding to ACE2. Hence, omicron and the recent BA.2.86 variant are relatively mild compared to the delta variant. Fourth, I will discuss binding to the human furin enzyme which plays a role in cleaving the spike protein to allow cell entry. The region of the spike protein which binds the enzyme is wholly different in SARS-CoV-2 compared to SARS-CoV-1 and this helps explain the deadliness of the newer virus. By using a combination of the new AlphaFold protein folding prediction program with molecular dynamics, our group was able to show that the delta variant has the strongest furin binding of any virus we have examined to within statistical accuracy.  Although the BA.2.86 variant is similar in this region to delta, the weak binding to ACE2 would appear to offset the threat. These binding stories lead to a natural conclusion that the delta variant is likely to be the worst the virus will provide absent large scale changes of the genome, supporting the consensus that we have moved into a lower risk endemic stage with the newer variants.