Rational design of small molecules

We are using state-of-the-art alchemical free energy calculations coupled with robotic biophysical experiments to probe the physical determinants of small molecule binding and selectivity.

Using our code YANK, built on the GPU-accelerated OpenMM molecular simulation library, we explore new algorithms for enhanced sampling (such as replica-exchange and self-adjusted mixture sampling) and increased chemical detail (including dynamic treatment of protonation states and counterions).

Using robotically driven site-directed mutagenesis to perturb the protein, rather than synthesize new small molecules, we can rapidly collect data to improve algorithms, forcefields, and the treatment of chemical effects in protein-ligand modeling, as well as address fundamental physical questions about what interactions are critical in determining small molecule affinity and selectivity.

 Imatinib binding to Src kinase [2OIQ].

Imatinib binding to Src kinase [2OIQ].

Functional biomolecular dynamics

We are developing statistical kinetic models to study the impact of small molecule binding on biomolecular function and regulation.

We use a number of technologies, including the worldwide distributed computing network Folding@Home, GPU-accelerated supercomputers like ORNL Titan and Blue Waters, and local GPU cluster resources to collect massive quantities of molecular simulation data for biomolecular targets of interest.  We couple this with the powerful framework of Markov state models to build statistical models of biomolecular dynamics and understand how small-molecule binding perturbs dynamics and function.


Multiscale modeling of cellular pathways

We are working to develop true multiscale methods that bridge atomistic models with biochemical pathways to predict the complex effects of imperfectly selective drugs.

We use and extend techniques like Greens function reaction dynamics (GFRD) to model systems where small copy numbers, spatial heterogeneity, and stochastic noise are critical to understanding signal transduction.


Kinase inhibitor selectivity and design

We are performing kinome-wide computational and experimental studies as a route to design kinase inhibitors with desired selectivity profiles.

Useful tools:

 Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com)

Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com)

Rational design of allosteric modulators

We are developing new computational techniques to facilitate the design of small molecule allosteric modulators, allowing the exploitation of binding pockets not previously characterized by structural biology techniques.

We are currently applying these techniques to target Ras, a small GTPase found to mutate in 20-30% of all human tumors.

 H-Ras GTPase [5P21] with GTP analog.

H-Ras GTPase [5P21] with GTP analog.