Our proposed studies aim to continue development of the 1-dynamics methodology to free energy-based calculations of ligand-protein interactions. Specifically, (i) we will extend and develop the 1- dynamics approach for screening of multiple ligands in a common receptor. Furthermore (ii) we will develop new methods to permit """"""""combinatorial"""""""" searches through chemical functional groups at multiple sites of diversity on a common framework bound in a common receptor, thereby implementing a free energy-based """"""""combinatorial library"""""""" assessment screen. Testing of these methods will be carried out on a series of heterocyclic ligands that bind to an engineered cavity in cytochrome c peroxidase (CCP). We will utilize the extensive database of compounds bound to the mutant W191G mutant CCP, for which Goodin and his colleagues have characterized both structure and binding thermodynamics. New methods to explore the development of starting structures for ligands bound to proteins will also be emphasized. Our approaches to """"""""ligand-docking"""""""" will exploit preliminary studies which systematically explore energy functions and docking protocols on a test set of five known ligand-receptor complexes with varying complexity. Finally, applications of these methods, both docking and free energy simulations will be made in two main areas. The first involves the role of electrostatic interactions in stabilizing heterocyclic ring systems in the cavity engineered into CCP. In collaboration with D. Goodin and his group, we will explore the requirements for strong ligand binding and attempt design of ligands that permit oxidative chemistry to take place on such ligands. A second area of investigation will exploit ongoing studies of our colleagues, Wong and Elder, to examine the thermodynamic and structural requirements for the development of HIV protease inhibitors that show """"""""resistance to resistance"""""""". We will utilize structural and thermodynamic studies on proteases from HIV and FIV as starting points for free energy based modeling of interactions in these systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM037554-14
Application #
2743758
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1986-12-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Ding, Xinqiang; Hayes, Ryan L; Vilseck, Jonah Z et al. (2018) CDOCKER and ?-dynamics for prospective prediction in D?R Grand Challenge 2. J Comput Aided Mol Des 32:89-102
Ding, Xinqiang; Vilseck, Jonah Z; Hayes, Ryan L et al. (2017) Gibbs Sampler-Based ?-Dynamics and Rao-Blackwell Estimator for Alchemical Free Energy Calculation. J Chem Theory Comput 13:2501-2510
Su, Min; Guo, Emily Z; Ding, Xinqiang et al. (2017) Mechanism of Vps4 hexamer function revealed by cryo-EM. Sci Adv 3:e1700325
Hayes, Ryan L; Armacost, Kira A; Vilseck, Jonah Z et al. (2017) Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite ? Dynamics. J Phys Chem B 121:3626-3635
Kim, Seonghoon; Lee, Jumin; Jo, Sunhwan et al. (2017) CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules. J Comput Chem 38:1879-1886
Won, Sang Joon; Davda, Dahvid; Labby, Kristin J et al. (2016) Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2). ACS Chem Biol 11:3374-3382
Mustoe, Anthony M; Al-Hashimi, Hashim M; Brooks 3rd, Charles L (2016) Secondary structure encodes a cooperative tertiary folding funnel in the Azoarcus ribozyme. Nucleic Acids Res 44:402-12
Lee, Jumin; Cheng, Xi; Swails, Jason M et al. (2016) CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput 12:405-13

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