We are computational scientists who focus on chemical biology, the interactions between small molecules and biological macromolecules. We develop and apply new methods that may be helpful for structure-based drug design.
Much, but not all, of our effort is based on implicit ligand theory (ILT), a theoretical framework for binding free energies which David derived in 2012. Most binding free energy calculations involve computationally expensive molecular simulations of flexible binding partners. David showed that, in theory, equally good results may be achieved by computing free energies between flexible ligands and multiple rigid receptor configurations.
Some of our achievements are described below.
Although it is well-known that ligands are polarized by proteins, the magnitude of this effect had not been quantified in many systems. We evaluated the ligand polarization energy for several hundred protein-ligand complexes and showed that it is a large and highly variable component of the binding energy.
The binding potential of mean force (BPMF), the binding free energy between a flexible ligand and a rigid receptor, is a critical ingredient for esimating binding free energies with implicit ligand theory. We have written software to precisely estimate this quantity and tested it on a diverse set of 85 protein-ligand complexes.
Although there are many ways to select representative snapshots from a molecular dynamics simulation to perform molecular docking, it has been unclear how to assess these methods. We pointed out that this procedure is an example of a statistical method, stratified sampling, and that the efficiency of stratification can be used to assess ensemble reduction methods.
We have shown that the Fast Fourier transform can be used to calculate binding free energies using implicit ligand theory. Previously, the use of FFT in molecular docking was only to estimate interaction energies.
We have identified the ubiquinone binding site in the bacterial ion pump NQR. This binding site is not obvious from the crystal structure. It is a possible target for structure-based drug design.
See article in IIT Today.
We have shown how to use constrained molecular dynamics, such as torsional dynamics, as a Monte Carlo move for molecular simulation. Previously, molecular simulations based on constrained dynamics would not sample from the appropriate distribution or not sample the entirely of configuration space.
See article in IIT Today.
We have performed large-scale protein-ligand binding free energy calculations using implicit ligand theory. Previously, implicit ligand theory was only applied to host-guest systems.
We have shown that if there are a sufficient number of states in a replica exchange simulation, the precise definition of states does not affect sampling efficiency. Previously, many scientists thought that the number of states in replica exchange should be carefully optimized.
This website contains information about: our research projects in fast binding free energy calculations, enhanced sampling methods, Bayesian analysis of binding experiments, and modeling metabolic enzymes from pathogenic bacteria; a complete list of our publications from the lab and David’s prior work; links to source code and data related to publications and classes; links to recommended software; a nascent scientific blog; and finally information about our members, alumni, and visiting or joining the lab.
Our research has been supported by
Robert E. Frey, Jr.
David presents implicit ligand theory for the Theoretical and Computational Biophysics Group at UIUC.
August 24, 2020Welcome to Jaycee, Joseph, Sophie, and Ella, our new Ph.D. students!
July 16, 2020Oscar Juarez, Karina Tuz, and David file a patent for CROWNase, a potential COVID-19 treatment. The technology transfer office has made a nonconfidential summary available.
June 1, 2020David designated as the inaugural Robert E. Frey, Jr. Term Chair in Chemistry.
April 6, 2020Congratulations, Jim, on passing your Ph.D. qualifying exam!
March 1, 2020Congratulations, Soohaeng, on your promotion to Research Assistant Professor!
December 29, 2019Congratulations, Bing, on your postdoctoral position at the NIH!
September 11, 2019David selected as one of 40 under 40 Chicago Scientists by Halo Cures.
April 16, 2019David honored with a Junior Faculty Award.
April 5, 2018David awarded tenure and promotion.
December 12, 2018David honored with a College of Science Dean's Excellence Award.
August 16, 2018We were awarded a NIH R01 grant for fast binding free energy calculations.
April 12, 2018We published a new version of implicit ligand theory for relative binding free energies.
January 30, 2018David named the Associate Director of the Center for Interdisciplinary Scientific Computation.
September 26, 2017We published a method for using constrained dynamics in equilibrium simulation.
July 18, 2017We discovered a substrate binding site in an important bacterial ion pump.
May 10, 2017Chen selected as a “CBSB2017 Outstanding Young Researcher”.
October 20, 2015We were awarded a NIH grant on implicit ligand theory.
August 13, 2015David to help host the Midwest Enzyme Chemistry Conference at IIT.
April 28, 2015John awarded a Undergraduate Summer Research Stipend. Congratulations!
