COVID-19 Research: University Of California-Irvine Scientists Discover Distant Residues That Modulate Conformational Openings In SARS-CoV-2 Spike Protein

COVID-19 Research: Scientists from University Of California-Irvine have discovered that distant residues modulate the conformational openings in SARS-CoV-2 spike protein.  The researchers also warn that the mutations in these residues could generate new coronavirus strains with different degrees of infectivity and virulence, resulting in future epidemics. 


 
The study team says that Infection of human cells by the SARS-Cov-2 coronavirus involves the attachment of the receptor binding domain (RBD) of the spike protein to the peripheral membrane ACE2 receptors. The process is initiated by a down to up conformational change in the spike presenting the RBD to the receptor.
 
So far early stage computational and experimental studies on potential therapeutics have concentrated on the receptor binding domain, although this region is prone to mutations with the possibility of giving rise to widespread drug resistance.
 
The study team utilizing atomistic molecular dynamics simulation, studied the correlations between the RBD dynamics with physically distant residues in the spike protein, and provides a deeper understanding of their role in the infection, including the prediction of important mutations and of distant allosteric binding sites for therapeutics.
 
Their model, based on time-independent component analysis (tICA) and protein graph connectivity network, was able to identify multiple residues, exhibiting long-distance coupling with the RBD opening dynamics. Mutation on these residues can lead to new strains of coronavirus with different degrees of infectivity and virulence. The most ubiquitous D614G mutation is predicted ab-initio from their model. Conversely, broad spectrum therapeutics like drugs and monoclonal antibodies can be generated targeting these key distant regions of the spike protein
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.12.07.415596v1
 
The SARS-CoV-2 has infected over 71.8 million individuals worldwide and has claimed more than 1.6 million lives. While various vaccines are already developed and being administered to frontline health workers, and vulnerable individuals, the drug design progression against this infection is still in its infancy.
 
This study in context focuses on the receptor-binding domain (RBD) of the spike protein of the SARS-CoV-2. A wide array of spike proteins envelope the virus, resembling a corona.
 
These spike proteins are the key infection machinery of the SARS-CoV-2 virus. They bind to the host receptors (angiotensin-converting enzyme 2, ACE2), enabling the virus's entry into the host. However, the spike is prone to mutations that may lead to resistance against drug therapeutics.
 
Properly comprehending the spike protein's functioning will enable an effective therapeutics design for SARS-CoV-2 and other probable SARS epidemics in the future.
 
Dr Dhiman Ray, Dr Ly Le, and Dr Ioan Andricioaei, from the Department of Chemistry and the Department of Physics, University of California-Irvine, present an insight into the RBD dynamics with physically distant residues in the spike pro tein, elaborating on the importance of predicted mutations and distant allosteric binding sites for therapeutics.
 
Their research primarily focuses on the effect of distant residues on the dynamics of the spike protein's structural transition leading to the RBD-up conformation.
 
The study team presented this as the RBD opening transition in the SARS-CoV-2 spike protein: undergoing the down to up transition leading to the binding to the human ACE2 receptor. If this binding is inhibited altogether, there is a higher degree of barrier towards the infection.
 
In order to identify the distant residues that show correlated motion coupled to RBD opening and closing dynamics, the study team used a novel approach: correlating backbone dihedral angles with the slowest independent component, which could identify a small number of non-RBD residues strongly influencing the conformational change of the spike.
 
Utilizing free energy profile of the RBD dynamics, quantifying the correlation of the backbone torsion angles of the protein, and studying allosteric connections by constructing a dynamical network model, they predict a few residues in specific regions of the S protein that may play a crucial role in the spike protein RBD dynamics.
 
The study team applied a time-independent component analysis (tICA) and protein graph connectivity network on all-atom molecular dynamics trajectories. It can identify multiple residues, exhibiting long-distance coupling with the RBD opening dynamics.
 
The study team identified that critical non-RBD residues play a crucial role in the conformational transition facilitating spike-receptor binding and of the human cell infection.
 
Importantly broad-spectrum antibodies and drugs cannot target these residues. The authors also warn that the mutations in them can generate new coronavirus strains with different degrees of infectivity and virulence, resulting in future epidemics. They predict the most ubiquitous D614G mutation.
 
The study team performed molecular dynamics simulation and tICA and graph theory-based analysis to identify the role of physically distant residues in the dynamics of the receptor-binding domain in the SARS-CoV-2 spike protein.
 
Dr Dhiman Ray told Thailand Medical News, “From the point of view of immediate therapeutic application, this study opens up the possibility of designing inhibitors that bind to the regions outside RBD and can prevent infection by freezing the RBD dynamics by applying steric restrictions on the distant residues.”
 
Most importantly the evolutionary adaptations taken by the SARS-CoV-2 coronavirus to evade the immune response need to be well understood.
 
Any mutations in critical residues can change the infectivity and the virulence - significantly altering the pandemic's course. Research enabling a better understanding of the viral protein and its functioning will help better drug and therapeutics design and prevent future outbreaks.
 
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