Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its spike (S) glycoprotein to bind angiotensin-converting enzyme 2 (ACE2) for cell entry.
• The receptor-binding domain (RBD) within the S protein mediates this critical interaction.
• S protein dynamics and conformational states influence the accessibility of the ACE2-binding site.

Approach:

• Single-molecule Förster resonance energy transfer (smFRET) imaging was employed to study the conformational dynamics of the SARS-CoV-2 S protein.
• The study examined S protein from the Wuhan-1 strain and the B.1 variant (D614G).
• Fluorescence correlation spectroscopy (FCS) was used for solution-based binding experiments.

Key Points:

• The D614G mutation in the B.1 variant alters the energetics of the RBD position, similar to ACE2 binding.
• Antibodies targeting various epitopes, including those not directly at the RBD, stabilize the RBD in an ACE2-competent conformation.
• Antibody binding was shown to enhance the binding affinity of ACE2 to the S protein.

Conclusions:

• Antibody binding can allosterically modulate SARS-CoV-2 spike protein conformation to facilitate ACE2 interaction.
• These findings provide insights into the mechanisms of antibody action against SARS-CoV-2.
• The results support the development of therapeutic antibody cocktails targeting viral entry mechanisms.