(150f) Effect of Mutation on Dynamic Conformations and Druggability of KRAS Protein

Kirsten Rat Sarcoma (KRAS) is recognized as one of the most relevant protein targets for cancer therapeutics because of its critical role in cancer development. However, the development of drugs targeting KRAS remains challenging due to a limited understanding of the effect of the mutation on the dynamic conformation of the KRAS proteins. This work will present our efforts to enhance the discovery of drugs that target KRAS proteins. We first investigate the dynamic conformation of three KRAS mutants (G12C, G12D, and G12V) using molecular dynamics simulations and accelerated molecular simulations. The focus is on revealing the mutation-induced variation in the residue-residue interaction network and the protein conformation and flexibility. We also predict the potential allosteric sites on the three KRAS mutants using an integration of the structure-aware protein language models developed in our group and MD simulations. In addition, we deploy deep learning-based molecular docking to search for potential small molecule candidates that may bind to the predicted allosteric sites of the three KRAS mutants.