Research Projects

One major emphasis is binding prediction

A major focus is the binding of small-molecule ligands to proteins. While current computational methods see widespread use in the pharmaceutical industry in drug discovery applications, accuracy is limited and these approaches fall far short of the goal of using computers to suggest new drug candidates. Methods we recently developed and applied have achieved far greater accuracies at computing and even predicting binding affinities than previous methods, so we are working to begin applying these in more complicated and pharmaceutically relevant binding sites. Projects involve both applications to drug discovery problems, and methodological improvements. Our work in this area focuses on using so-called alchemical free energy techniques for predicting binding affinities using molecular simulations. (See for more.)

We continue to advance methods for binding prediction using model binding sites:

Previously, we pioneered techniques for computing absolute binding free energies, applying these first in several model binding sites -- an apolar binding site in T4 lysozyme, and then in more polar version of the binding site which introduces hydrogen bonding. This included work on handling uncertainty in ligand binding modes. Continuing the progression towards biological binding sites, we just completed work (now in review) on two different charged designed binding sites in Cytochrome C peroxidase, which involve some new methodological challenges. And, bridging between model and biological binding sites, we are studying binding of a series of small molecules in the charged binding site of trypsin, a serine protease. We are also revisiting the lysozyme binding sites to test a variety of enhanced sampling methods to improve the overall efficiency of binding free energy calculations.

We apply binding free energy techniques

We have several more application-oriented problems of binding free energy techniques. These include several collaborations with experimental groups:

We make free energy calculations easier to apply:

A major bottleneck in using these calculations in a drug discovery setting has been the difficulty of setting them up, and the expertise required to do so. We are working on new tools to make free energy calculations dramatically easier to apply, including a tool for automated planning of relative free energy calculations, Lead Optimization Mapper (LOMAP -- DOI). We are also working on tools to automatically set up input files for these calculations, making them possible on a large scale as never before.

We run community tests of computational methods

We have a long history of involvement in the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) project, which focuses on blind tests of computational methods for predicting solvation, macromolecular interactions, and other properties. Our group has typically participated in the past, but in 2013 we organized the SAMPL4 challenge, which drew submissions from roughly 30 groups around the world in categories including HIV integrase binding, small-molecule solvation, and host-guest binding. We are seeking funding for future iterations of the SAMPL challenge.

More research projects...