Abstract
Protein-protein interactions coordinate functions within a cell making it fit to survive. Some of the proteins in this network of interactions act as hubs, interacting with many other proteins. A detailed understanding of the functioning of proteins, especially hub proteins, given its three-dimensional structure, is critical for drug development. Dynamics of proteins play a major role in these cases, as recognition of multiple ligands requires conformational diversity to form specific interactions to partner molecules. One hub-like protein is Cyclin-dependent kinases 2 or CDK2, whose primary function is to act as a cell-cycle checkpoint, and is particularly relevant to cancer progression. As a result, it has long been considered a drug target. Detailed analysis of its dynamics can help to understand how it binds to a drug molecule, or how it recognizes its partner protein Cyclin-E. Here, we show how two methods using molecular dynamics simulation (MD) and normal mode analysis (NMA) help us to address the above. We show that by using an advanced MD method, multicanonical MD, a drug molecule can be successfully docked into the pocket of CDK2 by fully exploring the conformational and configurational diversity. This enabled us to accurately estimate both the binding configuration and the affinity between the molecules. Next, we show the impact on the dynamics of Cyclin-E binding to CDK2 by using our custom implementation of NMA at the atomic level. We demonstrate the importance of insights gained into the dynamics of proteins via computational methods is crucial for understanding their function and behavior and for the development of drugs against cancer.
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Acknowledgments
This work was performed in part under the Cooperative Research Program of the Institute for Protein Research, Osaka University, CR-19-05 and CR-20-05 to N.K. and was supported by the Grand-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JP20H03229 and JP20K15758).
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Dasgupta, B., Bekker, GJ., Kamiya, N. (2021). Dynamical Methods to Study Interaction in Proteins Facilitating Molecular Understanding of Cancer. In: Chakraborti, S., Ray, B.K., Roychowdhury, S. (eds) Handbook of Oxidative Stress in Cancer: Mechanistic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-15-4501-6_149-1
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DOI: https://doi.org/10.1007/978-981-15-4501-6_149-1
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