Allosteric regulation in SARS-CoV-2 spike protein

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Allosteric regulation is crucial in protein-protein interactions and a key target for drug design.
• Previous studies indicated allosteric regulation within the SARS-CoV-2 spike protein.
• Understanding these allosteric pathways is vital for developing targeted therapies.

Purpose of the Study:

• To elucidate the specific routes of allosteric regulation in the SARS-CoV-2 spike protein.
• To identify key amino acids involved in allosteric communication pathways.
• To provide a foundation for designing novel allosteric inhibitors.

Main Methods:

• All-atom explicit solvent molecular dynamics simulations.
• Contrastive machine learning techniques.
• The Ohm approach for analyzing allosteric pathways.

Main Results:

• Peptide binding at polybasic cleavage sites activates spike protein backbone fluctuations.
• These fluctuations propagate to the receptor-binding domain (RBD), affecting ACE2 binding.
• Significant overlap (39-67%) exists between allosteric routes from cleavage sites and N-terminal domains, indicating a network.

Conclusions:

• A detailed map of allosteric regulation in the SARS-CoV-2 spike protein has been established.
• The findings reveal a coordinated allosteric network within the spike protein.
• This research facilitates the rational design of allosteric antibody inhibitors against SARS-CoV-2.