SARS-CoV-2 envelope protein attain K_ac mediated dynamical interaction network to adopt 'histone mimic' at BRD4...

Area of Science:

• Molecular biology
• Virology
• Structural biology

Background:

• Pathogen proteins can hijack host cellular machinery through molecular mimicry, a process involving the recognition of host-pathogen interactions.
• The SARS-CoV-2 envelope (E) protein is suggested to mimic host histones on the Bromodomain and Extra-Terminal domain-containing protein 4 (BRD4) surface, but the mechanism remains unclear.

Purpose of the Study:

• To elucidate the dynamic and structural mechanisms by which the SARS-CoV-2 E protein mimics host histones at the BRD4 surface.
• To investigate the role of specific residues and water-mediated interactions in this mimicry.
• To provide insights for developing BRD4-specific therapeutic interventions against SARS-CoV-2.

Main Methods:

• Extensive molecular docking and molecular dynamics (MD) simulations were performed.
• Comparative analysis of complexes involving histones (H3, H4), the E protein, and apo-BRD4.
• Detailed binding site analysis and identification of interaction networks.

Main Results:

• The E protein achieves 'interaction network mimicry' by orienting its acetylated lysine (Kac) similarly to histones, including crucial water-mediated interactions.
• Tyrosine residue Y59 of the E protein acts as an anchor, facilitating Kac positioning within the BRD4 binding site.
• The E protein requires a larger binding site volume, comparable to H4-BRD4, and establishes a stable interaction network mimicking histone binding.

Conclusions:

• The SARS-CoV-2 E protein effectively mimics host histones on the BRD4 surface via a detailed 'interaction network mimicry' mechanism.
• This mimicry involves specific residue interactions (e.g., Y59) and water bridges, strengthening the hypothesis of viral hijacking of host machinery.
• The findings offer a mechanistic understanding crucial for developing targeted BRD4-based therapies against SARS-CoV-2.