Chodera Research Group

Lab website

Members

Publications

Takeaways

The Chodera Group 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 moderate- and high-throughput experiments focusing on characterizing biophysical interactions between proteins and small molecules.

Current Research Topics:

  • Human kinome structural biology.  We are currently embarking on a massive project to simulate all human kinase catalytic domains on the Folding@home worldwide distributed computing platform to map out the conformational landscapes accessible to the human kinome.
  • Selective kinase inhibitors.  We are using state-of-the-art alchemical free energy calculations coupled with robotic biophysical experiments to probe the physical determinants of kinase inhibitor selectivity.
  • Emergence of drug resistance.  We are developing statistical models for the emergence of resistance mutations in kinase inhibitors, with the goal of engineering therapeutics (or combinations thereof) that are unlikely to elicit resistance.
  • Multiscale modeling of cellular pathways.  We are working to develop true multiscale methods that bridge atomistic models to biochemical pathways to predict the often complex effects of drugs with imperfect selectivity on cells.

Popular software and links

  • YANK – GPU-accelerated alchemical free energy calculations
  • pymbar – Python implementation of the multistate Bennett acceptance ratio (MBAR) method
  • NCMC – Nonequilibrium candidate Monte Carlo examples
  • alchemistry.org – best practices in alchemical free energy calculations