The noncovalent association of molecules in solution is of fundamental importance in biology and medicine. In particular, many medications work by binding to specific protein targets. For example, an important class of AIDS medications works by binding to and inhibiting the function of HIV-1 protease, an enzyme that is essential for the growth of the AIDS virus. Thus, research projects aimed at developing new medications often center around the discovery of molecules that bind a targeted protein. The present project seeks to develop theory and methods that will facilitate this step in drug-design, by developing a better understanding of the physical mechanisms of noncovalent binding, and by creating algorithms and computer programs that can be used to predict what molecules will bind to a selected molecular target.
The specific aims of this project include elucidation of the theory connecting molecular simulations with measured binding affinities; further development of a promising new class of algorithms for computing binding free energies; analysis and improvement of efficient models of the solvent for use in binding calculations; and validation of the new models against experimental data.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061300-02
Application #
6387160
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Flicker, Paula F
Project Start
2000-09-01
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$259,000
Indirect Cost
Name
University of MD Biotechnology Institute
Department
Type
Organized Research Units
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21202
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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