SARS-CoV-2 envelope protein attain K<sub>ac</sub> mediated dynamical interaction network to adopt ‘histone mimic’ at BRD4 interface
Creators: name: Agrahari, Ashish Kumar
name: Srivastava, Mitul
name: Singh, Mrityunjay
name: Asthana, Shailendra
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biophysics
subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Evolutionary Biology
subject: Science Policy
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Virology
subject: Computational Biology

description: Interface mimicry, achieved by recognition of host-pathogen interactions, is the basis by which pathogen proteins can hijack the host machinery. The envelope (E) protein of SARS-CoV-2 is reported to mimic the histones at the BRD4 surface via establishing the structural mimicry; however, the underlying mechanism of E protein mimicking the histones is still elusive. To explore the mimics at dynamic and structural residual network level an extensive docking, and MD simulations were carried out in a comparative manner between complexes of H3-, H4-, E-, and apo-BRD4. We identified that E peptide is able to attain an ‘interaction network mimicry’, as its acetylated lysine (Kac) achieves orientation and residual fingerprint similar to histones, including water-mediated interactions for both the Kac positions. We identified Y59 of E, playing an anchor role to escort lysine positioning inside the binding site. Furthermore, the binding site analysis confirms that E peptide needs a higher volume, similar to the H4-BRD4 where both the lysine’s (Kac5 and Kac8) can accommodate nicely, however, the position of Kac8 is mimicked by two additional water molecules other than four water-mediated bridging’s, strengthening the possibility that E peptide could hijack host BRD4 surface. These molecular insights seem pivotal for mechanistic understanding and BRD4-specific therapeutic intervention. 
KEY POINTSMolecular mimicry is reported in hijacking and then outcompeting the host counterparts so that pathogens can rewire their cellular function by overcoming the host defense mechanism.The molecular recognition process is the basis of molecular mimicry. The E peptide of SARS-CoV-2 is reported to mimic host histone at the BRD4 surface by utilizing its C-terminally placed acetylated lysine (K<sub>ac</sub>63) to mimic the N-terminally placed acetylated lysine K<sub>ac</sub>5GGK<sub>ac</sub>8 histone (H4) by <i>interaction network mimicry</i> identified through microsecond molecular dynamics (MD) simulations and post-processing extensive analysis.There are two steps to mimic: firstly, tyrosine residues help E to anchor at the BRD4 surface to position K<sub>ac</sub> and increase the volume of the pocket. Secondary, after positioning of K<sub>ac,</sub> a common durable <i>interaction network</i> N140:K<sub>ac</sub>5; K<sub>ac</sub>5:W1; W1:Y97; W1:W2; W2:W3; W3:W4; W4:P82 is established between K<sub>ac</sub>5, with key residues P82, Y97, N140, and four water molecules through water mediate bridge. Furthermore, the second acetylated lysine K<sub>ac</sub>8 position and its interaction as polar contact with K<sub>ac</sub>5 were also mimicked by E peptide through interaction <i>network</i> P82:W5; W5:K<sub>ac</sub>63; W5:W6; W6:K<sub>ac</sub>63.The binding event at BRD4/BD1 seems an induced-fit mechanism as a bigger binding site volume was identified at H4-BRD4 on which E peptide attains its better stability than H3-BRD4.We identified the tyrosine residue Y59 of E that acts like an anchor on the BRD4 surface to position K<sub>ac</sub> inside the pocket and attain the interaction network by using aromatic residues of the BRD4 surface. Molecular mimicry is reported in hijacking and then outcompeting the host counterparts so that pathogens can rewire their cellular function by overcoming the host defense mechanism. The molecular recognition process is the basis of molecular mimicry. The E peptide of SARS-CoV-2 is reported to mimic host histone at the BRD4 surface by utilizing its C-terminally placed acetylated lysine (K<sub>ac</sub>63) to mimic the N-terminally placed acetylated lysine K<sub>ac</sub>5GGK<sub>ac</sub>8 histone (H4) by <i>interaction network mimicry</i> identified through microsecond molecular dynamics (MD) simulations and post-processing extensive analysis. There are two steps to mimic: firstly, tyrosine residues help E to anchor at the BRD4 surface to position K<sub>ac</sub> and increase the volume of the pocket. Secondary, after positioning of K<sub>ac,</sub> a common durable <i>interaction network</i> N140:K<sub>ac</sub>5; K<sub>ac</sub>5:W1; W1:Y97; W1:W2; W2:W3; W3:W4; W4:P82 is established between K<sub>ac</sub>5, with key residues P82, Y97, N140, and four water molecules through water mediate bridge. Furthermore, the second acetylated lysine K<sub>ac</sub>8 position and its interaction as polar contact with K<sub>ac</sub>5 were also mimicked by E peptide through interaction <i>network</i> P82:W5; W5:K<sub>ac</sub>63; W5:W6; W6:K<sub>ac</sub>63. The binding event at BRD4/BD1 seems an induced-fit mechanism as a bigger binding site volume was identified at H4-BRD4 on which E peptide attains its better stability than H3-BRD4. We identified the tyrosine residue Y59 of E that acts like an anchor on the BRD4 surface to position K<sub>ac</sub> inside the pocket and attain the interaction network by using aromatic residues of the BRD4 surface. Communicated by Ramaswamy H. Sarma