Methods of computer-aided drug design
Advancing the technologies of computer-aided drug design (CADD) is a central theme of our work.
We are developing advanced methods of computing protein-small molecule binding thermodynamics, as well as new ways to think about and model the role of water structure in protein-ligand binding.
One of the factors that limits the accuracy of CADD methods is the approximate character of the potential functions, or force fields, that are at the foundation of many molecular modeling technologies. We are therefore engaged in a number of projects aimed at improving the accuracy of force fields. One approach involves synthesizing host-guest systems, small molecular recognition systems that are conceptually similar to protein-drug systems but are much easier to study experimentally and simulate. They are thus powerful and informative tools to test and improve force fields and simulation methods in general. We are also an active member lab of the Open Force Field Initiative and the associated Consortium.
Selected Publications
Simulating water exchange to buried binding sites. I Ben-Shalom, C Lin, T Kurtzman, RC Walker, MK Gilson. J Chem Theo Comput 15:2684, 2019, 10.1021/acs.jctc.8b01284
Facile synthesis of a diverse library of mono-3-substituted beta-cyclodextrin analogues. K Kellett, BM Duggan, MK Gilson. Supramolec Chem 31:251, 2019, 10.1080/10610278.2018.1562191
Evaluating force field performance in thermodynamic calculations of cyclodextrin host–guest binding: Water models, partial charges, and host force field parameters. NM Henriksen, MK GIlson. J Chem Theo Comput 13:4253, 2017, 10.1021/acs.jctc.7b00359.
Attach-pull-release calculations of ligand binding and conformational changes on the first BRD4 bromodomain. G Heinzelman, NM Henriksen, MK Gilson. J Chem Theo Comput 13:3260, 2017, 10.1021/acs.jctc.7b00275.
Evaluation and minimization of uncertainty in ITC binding measurements: heat error, concentration error, saturation, and stoichiometry. SA Kantonen, NM Henriksen, MK Gilson. Biochim Biophys Acta Gen Subj 1861:485, 2017, 10.1016/j.bbagen.2016.09.002.
Grid inhomogeneous solvation theory: hydration structure and thermodynamics of the miniature receptor cucurbit [7] uril. CN Nguyen, T Kurtzman, MK Gilson. J Chem Phys 137:044101, 10.1063/1.4733951.