Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

2-POS Board 2 SARS-COV-2 ENVELOPE PROTEIN ATTAIN KAC MEDIATED DYNAMICAL INTERACTION NETWORK TO ADOPT "HISTONE MIMIC" AT BRD4 INTERFACE Ashish Kumar K. Agrahari 1 ; 1 Translational Health Science and Technology Institute, Non Communicable Disease, Faridabad, Haryana, India, India Background Identification of structural determinants which hold the critical residues is the basis of the molecular recognition process, mapping them is essential for mechanistic understanding as well as can help to design therapeutic strategies. Interface mimicry, achieved by recognition of host–pathogen interactions, is the basis by which pathogen protein can hijack the host machinery by attaining the essential wiring via residual network. The envelope (E) protein of SARS-CoV-2 is known to mimic the histones at BRD4 surface via establishing the structural mimicry. However, it is still elusive as to how E protein is able to achieve the stable adduct competing with endogenous regulators such as histones. Experimental approach The extensive protein- peptide docking, followed by 7.3 micro-second MD simulations and its multifaceted post- processing analysis, we have done a comparative mapping of H3/H4/E over BRD4 surfaces. Results We identified that E protein is able to perform an “interaction network mimicry” as it attains the similar orientation of acetylated lysine (Kac) and residual wiring including water- mediated interactions at BRD4 surface. The multiple trajectories confirm the stability of E similar to histones, however, the comparable thermodynamics quantification rules out the possibility of E to outcompeting the histones in a competitive manner. Moreover, due to similar interaction network mimicry, stability of complex and comparable thermodynamics between E and histones, strengthen the possibility that E protein could hijack the host BRD4 surface. Conclusion Overall, this current study has opened up a new avenue for researchers to establish the mechanistic understanding and can be explored for therapeutic intervention by perturbing the interaction network mimicry.

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