Weill Medical College of Cornell University New York United States
The long-term objective of this project is to advance the understanding of the biology, therapeutic potential and availability of small molecule drugs for cancer-implicated histone lysine methyltransferases HKMTs EZH2 lymphoma and melanoma target and SETDB1 melanoma target. The immediate objective of this project is to present to the scientific community a number of novel small molecule binding modes and pockets in those protein targets, as well as novel small molecule chemical probe scaffolds to hit them. In this report, I show the preparation and data collection in tens of thousands of molecular dynamics trajectories on the distributed computing system Foldinghome, and generation of dynamic models of the conformational ensembles of EZH2 and EED, both in apo, and in-complex form PRC2 complex. I successfully deployed a semi-automatic Markov state model building pipeline on a pilot model system SETD8, hence creating a well sampled, prototypical Markov state model, from which to seed conformations for this project and extract reaction coordinates for adaptive and enhanced sampling simulation runs. I am continuing to refine the models, while building a small molecule ensemble pocket detection docking free energy calculations pipeline to select candidates for screening.