The overarching goal ? Computationally model biomolecular binding, iteratively informed by experiments, to fully understand molecular recognition and binding mechanisms, apply hidden free energy barriers to modify inhibitors for preferred binding kinetics, and use binding/unbinding free energy profiles to understand the role of waters and how and why residues far from ligand binding site can contribute to mutation effects and ligand selectivity. Non-covalent molecular recognition plays a crucial role in biology, chemistry and medicine. Kinetic binding rate constants, together with equilibrium constants, affect the speed, efficacy, and safety of non-covalent drugs and inform their design. In some cases, binding kinetics are the major determinant of a drug?s in vivo efficacy. However, kinetic behavior is mainly governed by transient unseen intermediates during ligand binding/unbinding processes, very difficult to observe experimentally. Computer simulations offer an alternative solution, both for describing and understanding experimentally unseen phenomena and to inform drug design. Real molecular systems are complicated and flexible and call for new modeling tools and theories to compute ligand binding/unbinding free energy profiles. Used in combination with experiments, our new modeling approach integrates data and interprets experiments as a precursor to designing molecules with preferred binding kinetics/affinities. Guided by excellent results obtained during the previous funding period, three Specific Aims are proposed: 1) Develop and apply methods to understand mechanisms and processes of molecular recognition that provide a comprehensive picture and applications for drug design; 2): Understand the binding/unbinding free energy profile from multiple pathways and investigate the effects of waters and sidechain mutations during recognition; 3) Adapt and apply the new methods to ligand binding specificity and kinetics to understand off-site kinase targets. The approach is innovative in its focus on control of kinetic behavior, advanced methods to realistically model free energy profiles and, based on this realism, expand on the classical view of molecular recognition. The proposed research is significant because it comprehensively models free energy profiles, kinetic behavior, detailed water effects, and mutations that may confer drug resistance. Significant outcomes: New computational tools to realistically design ligands with preferred binding kinetics, understand solvent and mutation effects, explain drug selectivity.

Public Health Relevance

The life time of drug occupancy on a protein target determines the duration of pharmacological action, and this lifetime is defined by dynamic processes that link to a drug binding to its target in clinically relevant environment. The key innovation in this proposal are novel computational tools to integrate molecular details for understanding binding kinetics and mechanisms to bring new knowledge for designing drugs with preferred function. Successful completion of these studies would lead to new insight into biomolecular binding and more efficiently design and discover strategies in drug development.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Lyster, Peter
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University of California Riverside
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United States
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Miao, Yinglong; Huang, Yu-Ming M; Walker, Ross C et al. (2018) Ligand Binding Pathways and Conformational Transitions of the HIV Protease. Biochemistry 57:1533-1541
Chang, Chia-En A (2018) Tuning Free Energy by Backbone Conformational Entropy: A Strategy from Disordered Proteins. Biophys J 114:2757-2758
Chen, Wei; Sun, Lipeng; Tang, Zhiye et al. (2018) An MM and QM Study of Biomimetic Catalysis of Diels-Alder Reactions Using Cyclodextrins. Catalysts 8:
You, Wanli; Chang, Chia-En A (2018) Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38? MAP Kinase Type-I/II/III Inhibitors. J Chem Inf Model 58:968-981
Bakas, Nicole A; Schultz, Chad R; Yco, Lisette P et al. (2018) Immunoproteasome inhibition and bioactivity of thiasyrbactins. Bioorg Med Chem 26:401-412
Tang, Zhiye; Chang, Chia-En A (2018) Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition. J Chem Theory Comput 14:303-318
Tang, Zhiye; Roberts, Christopher C; Chang, Chia-En A (2017) Understanding ligand-receptor non-covalent binding kinetics using molecular modeling. Front Biosci (Landmark Ed) 22:960-981
Miyata, Non; Tang, Zhiye; Conti, Michael A et al. (2017) Adaptation of a Genetic Screen Reveals an Inhibitor for Mitochondrial Protein Import Component Tim44. J Biol Chem 292:5429-5442
Tang, Zhiye; Chang, Chia-En A (2017) Systematic Dissociation Pathway Searches Guided by Principal Component Modes. J Chem Theory Comput 13:2230-2244
Huang, Yu-Ming M; Raymundo, Mark Anthony V; Chen, Wei et al. (2017) Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease. Biochemistry 56:1311-1323

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