Projects 10491-10499

Cause: cancer

In projects 10491-10499, the Chodera lab takes a look at mTOR, a serine/threonine kinase. The MTOR gene was originally discovered in yeast in 1991 and named TOR1/2 because it was the target of rapamycin, an anti-fungal small molecule isolated from the soil of Easter Island in the 1970s. In 1994, the mammalian target of rapamycin (mTOR) was discovered by Drs. Sabatini, Snyder, Abraham, and Schreiber.

mTOR integrates multiple signal inputs to control processes such as cell growth and metabolism, among others. Due to its role in controlling a number of cellular processes, mTOR has clinical significance in neurodegenerative diseases, diabetes and cancer. In the Chodera lab, we are working with the Hsieh lab at MSKCC to understand mTOR's role in cancer and the development of new and better therapeutics that target it.

Currently, the FDA has approved treatment for metastatic clear cell Renal Cell Carcinoma (ccRCC) that includes mTOR inhibitors such as Everolimus and Temsirolimus. An effort to understand the patient-to-patient variation in response to these drugs by studying extraordinary responders lead to the characterization of mTOR activating missense mutations in these patients. These mutants cluster in two domains of mTOR: the kinase and FAT domains. These projects will allow us to generate a model of the conformations available to mTOR and ultimately to investigate how these clinically relevant mutations might influence the protein’s structure.

Both the mTOR kinase domain and the larger construct including the FAT domain are very large systems, exploiting the latest OpenMM GPU core (0x21 v0.0.11) and push the capabilities of latest-generation GPUs to their full extent.

10491: MTOR kinase domain (80983 atoms, 40 snapshots/WU)
10492: MTOR kinase + FAT domains (277543 atoms, 40 snapshots/WU)
10495: MTOR kinase domain mutants (67842 atoms, 20 snapshots/WU) 
10496: MTOR kinase + FAT domain mutants (189218 atoms, 20 snapshots/WU) 

Gerstner Sloan Kettering graduate student Steven Albanese is the lead scientist behind this project.


List of Contributors

This project is managed by Prof. John Chodera at Memorial Sloan Kettering Cancer Center.

URL: http://choderalab.org

The Chodera lab uses computation and experiment to develop quantitative, multiscale models of the effects of small molecules on biomolecular macromolecules and cellular pathways. To do this, the group utilizes physical models and rigorous statistical mechanics, with overall goals of engineering novel therapeutics and tools for chemical biology, as well as understanding the physical driving forces behind the evolution of resistance mutations. The group makes use of advanced algorithms for molecular dynamics simulations on GPUs and distributed computing platforms, in addition to robot-driven high-throughput experiments focusing on characterizing biophysical interactions between proteins and small molecules.

A main focus of the lab is on the engineering of highly selective targeted small molecule inhibitors in cancer.

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