Dynamic Asymmetry Exposes 2019-nCoV Prefusion Spike

Area of Science:

• Structural Biology
• Virology
• Computational Biophysics

Background:

• The SARS-CoV-2 (COVID-19) pandemic is caused by the novel coronavirus (2019-nCoV).
• The viral spike protein mediates host cell entry, making it a critical target for therapeutic interventions.
• Understanding the spike protein's conformational dynamics is essential for developing effective treatments.

Purpose of the Study:

• To investigate the conformational energy landscape of the full-length prefusion 2019-nCoV spike protein.
• To elucidate the dynamic conformational strategies employed by the spike protein during host cell interaction.
• To identify key interactions stabilizing critical spike protein conformations.

Main Methods:

• Development of a symmetry-information-loaded structure-based Hamiltonian.
• Utilizing recent Cryo-EM structural data.
• Exploration of the complete conformational energy landscape.

Main Results:

• The 2019-nCoV prefusion spike protein exhibits dynamic conformational asymmetry.
• Two prevalent asymmetric structures were identified, featuring rotated spike heads for enhanced receptor binding.
• Unique interchain interactions at the NTD-RBD interface were found to stabilize the RBD 'up' conformation.

Conclusions:

• The identified dynamic asymmetry and stabilizing interactions provide crucial insights into 2019-nCoV spike protein function.
• This knowledge can inform the design of novel therapeutic strategies targeting viral entry.
• Understanding these molecular mechanisms is key to combating the COVID-19 pandemic.