Identifying a small molecule that tightly binds a targeted protein is a time-consuming, costly step in many drug discovery projects. Explicit solvent free energy methods can be used to predict small molecule-protein binding affinities and thus assist with this step. However, they do not provide consistently accurate predictions, and limitations in the force fields they use are implicated as a key source of error. Our main goal, therefore, is to help generate more trustworthy force fields. In particular, we aim to prove principle for the use of experimental binding data for host-guest systems, along with traditionally used liquid properties, to refine force field parameters. We also aim show that free energy methods can help predict ligand binding poses and rank compound libraries against targeted proteins. First, we will expand the chemical diversity of host-guest systems, by developing facile methods of derivatizing cyclodextrin host molecules, and using these methods to create new, water- soluble cyclodextrin derivatives. We will measure their binding free energies and enthalpies with varied guest molecules, and will use these new data to test and refine force fields. We also aim to prove principle for the use of sensitivity analysis to refine Lennard-Jones (LJ) parameters in existing atom-typed force fields, based on host-guest binding data and liquid property data. In addition to adjusting existing atom-typed parameters, we will develop an atoms-in-molecules approach to mapping a quantum calculation for a molecule to LJ parameters for that molecule. By reducing the number of parameters, relative to atom-typed methods, this approach should enable global parameter optimization, rather than just refinement of existing parameters. Finally, we will automate and optimize our lab?s attach-pull-release (APR) method of computing binding free energies so that it can be used to rank candidate poses of a ligand in a binding site; the most stable few poses will then be used for full binding free energy calculations. Success in this effort will enable free energy methods to be used in virtual compound screening. In addition, we will use the APR method to test the new parameters generated above in the context of protein-ligand binding.

Public Health Relevance

We aim to help pharmaceutical scientists develop new medications more quickly and at lower cost, by improving the accuracy of the computational methods used to design drugs. We will do this chiefly by generating more relevant experimental data, and using these data in new ways to refine the methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061300-19
Application #
9770891
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Lyster, Peter
Project Start
2000-09-01
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kantonen, Samuel A; Henriksen, Niel M; Gilson, Michael K (2018) Accounting for apparent deviations between calorimetric and van't Hoff enthalpies. Biochim Biophys Acta Gen Subj 1862:692-704
Mobley, David L; Bannan, Caitlin C; Rizzi, Andrea et al. (2018) Escaping Atom Types in Force Fields Using Direct Chemical Perception. J Chem Theory Comput 14:6076-6092
Chen, Shin-Fu; Huang, Nan-Lan; Lin, Jung-Hsin et al. (2018) Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate. Nat Commun 9:3085
Yin, Jian; Henriksen, Niel M; Muddana, Hari S et al. (2018) Bind3P: Optimization of a Water Model Based on Host-Guest Binding Data. J Chem Theory Comput 14:3621-3632
Li, Amanda; Gilson, Michael K (2018) Protein-ligand binding enthalpies from near-millisecond simulations: Analysis of a preorganization paradox. J Chem Phys 149:072311
Slochower, David R; Gilson, Michael K (2018) Motor-like Properties of Nonmotor Enzymes. Biophys J 114:2174-2179
Yin, Jian; Henriksen, Niel M; Slochower, David R et al. (2017) The SAMPL5 host-guest challenge: computing binding free energies andĀ enthalpies from explicit solvent simulations by the attach-pull-release (APR) method. J Comput Aided Mol Des 31:133-145
Reany, Ofer; Li, Amanda; Yefet, Maayan et al. (2017) Attractive Interactions between Heteroallenes and the Cucurbituril Portal. J Am Chem Soc 139:8138-8145
Henriksen, Niel M; Gilson, Michael K (2017) Evaluating Force Field Performance in Thermodynamic Calculations of Cyclodextrin Host-Guest Binding: Water Models, Partial Charges, and Host Force Field Parameters. J Chem Theory Comput 13:4253-4269
Kantonen, Samuel A; Henriksen, Niel M; Gilson, Michael K (2017) Evaluation and Minimization of Uncertainty in ITC Binding Measurements: Heat Error, Concentration Error, Saturation, and Stoichiometry. Biochim Biophys Acta Gen Subj 1861:485-498

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