This project aims to develop new computational tools that will speed structure-based drug-discovery by providing a detailed analysis of hydration structure and thermodynamics of water in targeted protein binding pockets. The fundamental concept is to discretize the equations of inhomogeneous solvation theory (IST), up to second order, onto 3D grids of energy and entropy in a targeted binding site. These grids will be populated by molecular dynamics (MD) simulations with explicit solvent. The resulting treatment of solvation, termed GIST, will be characterized through comparisons with experimental data and rigorous thermodynamic integration free energy calculations for protein binding pockets. The GIST method will be incorporated into visualization tools to highlight binding site regions where it is particularly favorable or unfavorable to displace solvent, in order to speed ligand design and evaluate the druggability of protein binding pockets. It will also be integrated into fast new functions for ligand docking and scoring, for which promising preliminary results are provided in this proposal. Finally, in order to maximize scientific and health impact, the software will be packaged, documented and disseminated as part of the freely available, widely used and open source AMBER Tools software suite.
Most medications are molecules that work by binding tightly to a specific pocket in the surface of a protein involved in a disease process, and thus blocking the protein's disease-related function. This project aims to develop advanced computational methods that will speed the discovery of new medications by helping scientists design molecules that will bind tightly to a targeted protein. We will develop concepts and software that will reveal the 3D patterning of water molecules in a targeted binding pocket and will use this information about water to pinpoint areas in the binding pocket to which a potential medication can stick particularly tightly.
|Haider, Kamran; Cruz, Anthony; Ramsey, Steven et al. (2018) Solvation Structure and Thermodynamic Mapping (SSTMap): An Open-Source, Flexible Package for the Analysis of Water in Molecular Dynamics Trajectories. J Chem Theory Comput 14:418-425|
|Pal, Rajat Kumar; Haider, Kamran; Kaur, Divya et al. (2017) A combined treatment of hydration and dynamical effects for the modeling of host-guest binding thermodynamics: the SAMPL5 blinded challenge. J Comput Aided Mol Des 31:29-44|
|Balius, Trent E; Fischer, Marcus; Stein, Reed M et al. (2017) Testing inhomogeneous solvation theory in structure-based ligand discovery. Proc Natl Acad Sci U S A 114:E6839-E6846|
|Haider, Kamran; Wickstrom, Lauren; Ramsey, Steven et al. (2016) Enthalpic Breakdown of Water Structure on Protein Active-Site Surfaces. J Phys Chem B 120:8743-56|
|Ramsey, Steven; Nguyen, Crystal; Salomon-Ferrer, Romelia et al. (2016) Solvation thermodynamic mapping of molecular surfaces in AmberTools: GIST. J Comput Chem 37:2029-37|
|Wickstrom, Lauren; Deng, Nanjie; He, Peng et al. (2016) Parameterization of an effective potential for protein-ligand binding from host-guest affinity data. J Mol Recognit 29:10-21|
|Nguyen, Crystal N; Kurtzman, Tom; Gilson, Michael K (2016) Spatial Decomposition of Translational Water-Water Correlation Entropy in Binding Pockets. J Chem Theory Comput 12:414-29|
|Nguyen, Crystal N; Cruz, Anthony; Gilson, Michael K et al. (2014) Thermodynamics of Water in an Enzyme Active Site: Grid-Based Hydration Analysis of Coagulation Factor Xa. J Chem Theory Comput 10:2769-2780|
|Nguyen, Crystal N; Young, Tom Kurtzman; Gilson, Michael K (2012) Grid inhomogeneous solvation theory: hydration structure and thermodynamics of the miniature receptor cucurbituril. J Chem Phys 137:044101|