Understanding Protein-Protein Interaction in CDK1/Cyclin B and SARS-COV-2-RBD/ACE2 protein complex
In many diseases, protein-protein interactions (PPIs) in the functional protein complexes are found to be dysregulated, so understanding PPI and their regulation will help in designing the drug molecules to tackle these PPIs and hence disease. Here we have studied the PPI in two protein complexes, CDK1/cyclin B and SARS-COV-2-SPIKE/ACE2.
The protein-protein binding in CDK1-cyclin B which is an essential cell cycle regulator 1 is known to be a default process. Our molecular dynamics (MD) simulation result suggest that PPI between them is not a default process rather regulated by acetylation and ATP binding in CDK1. Based on this evidence, we propose the formation of the CDK1-cyclin B complex, first through deacetylation of CDK1 and then Cyclin B binding in presence of ATP.
The receptor-binding domain (RBD) in SPIKE protein from the SARS-COV-2 virus interacts with human cell receptor protein ACE2 and this interaction acts as an entry point for the virus into the human cell 2. The interaction of ACE2 with RBD is mainly dominated by a helix called SBP1 3 which opens a route for disrupting PPI between SPIKE and ACE2 through designing an inhibitor based on SBP1 peptide. However, it has been reported that removing the SBP1 helix from ACE2 disrupts the helicity of SBP1. So, to tackle this, we have applied a lactam group based linker on SBP1 and studied the linker position-dependent stability of SBP1. We found that stapling at specific positions in the SBP1 peptide drastically improved its helicity.
1-N. R. Brown, S. Korolchuk, M. P. Martin, W. A. Stanley, R. Moukhametzianov, M. E. Noble, and J. A. Endicott, “CDK1 structures reveal conserved and unique features of the essential cell cycle CDK ”, Nature Communications, vol. 6, pp. 1–12, 2015.
2-Renhong Yan, Yuanyuan Zhang, Yaning Li, Lu Xia, Yingying Guo, Qiang Zhou, “Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 ”, Science, vol. 367, pp. 1444-1448, 2020.
3-G. Zhang, S. Pomplun, A. R. Loftis, A. Loas, B. L. Pentelute “The first-in-class peptide binder to the SARS-CoV-2 spike protein’’ bioRxiv 2020.03.19.999318