The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 68.2 million people worldwide and has claimed more than 1.56 million lives. While vaccines are developed and administered to frontline health workers, the drug design progression against this infection is still in its infancy.
The structure of the spike monomer with residues colored according to their degrees of variability over different strains. Image Credit: https://www.biorxiv.org/content/10.1101/2020.12.07.415596v1.full.pdf
Research in this 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.
Understanding the spike protein's functioning will enable an effective therapeutics design for SARS-CoV-2 and other probable SARS epidemics in the future.
Dhiman Ray, Ly Le, and Ioan Andricioaei, from the Department of Chemistry and the Department of Physics and Astronomy, from the University of California, present an insight into the RBD dynamics with physically distant residues in the spike protein, elaborating on the importance of predicted mutations and distant allosteric binding sites for therapeutics. Their work was recently published in a bioRxiv preprint.*
This study focuses on the effect of distant residues on the dynamics of the spike protein's structural transition leading to the RBD-up conformation. They present 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, the authors write.
To identify the distant residues that show correlated motion coupled to RBD opening and closing dynamics, the authors 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.
Using 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.
In this study, the authors 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. They identified that critical non-RBD residues play a crucial role in the conformational transition facilitating spike-receptor binding and of the human cell infection.
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.
In this study, the authors 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.
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.”
The evolutionary adaptations taken by the virus to evade the immune response need to be well understood. Mutations in critical residues can change the infectivity and the virulence - significantly altering the pandemic's course. Studies enabling a better understanding of the viral protein and its functioning will help better drug design and prevent future outbreaks.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.