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Dissertation/Thesis Abstract

Integrating conformational and protonation equilibria in biomolecular modeling
by Kim, Meekyum Olivia, Ph.D., University of California, San Diego, 2015, 192; 3709257
Abstract (Summary)

Due to high sensitivity of biomolecular systems to the electrostatic environments, coupled treatment of conformational and protonation equilibria is required for an accurate characterization of true ensemble of a given system. The research presented in this dissertation examines the effects of conformational and protonation equilibria of varying extent on diverse aspects of computational biomolecular modeling, as introduced in Chapter 1. The effects of protonation and stereoisomerism of two histidines on virtual screening against the M. tuberculosis enzyme RmlC are presented in Chapter 2. In Chapter 3, conformational flexibility of three M. tuberculosis prenyl synthases is probed using molecular dynamics simulations, with implications for computer-aided drug discovery effort for the new generation antibacterial and antivirulence therapeutics. Chapters 4 and 5 consider the conformational and protonation equilibria simultaneously by utilizing constant pH molecular dynamics, in which fluctuations in both conformation and protonation state are possible. In Chapter 4, a computational protocol utilizing constant pH molecular dynamics to compute pH-dependent binding free energies is presented. The methodology is further applied to protein-ligand complexes in Chapter 5, where the thermodynamic linkage between protonation equilibria, conformational dynamics, and inhibitor binding is illustrated.

Indexing (document details)
Advisor: McCammon, James A.
School: University of California, San Diego
Department: Chemistry
School Location: United States -- California
Source: DAI-B 76/11(E), Dissertation Abstracts International
Subjects: Physical chemistry, Biophysics
Keywords: Conformational eqilibria, Drug discovery, Protonation equilibria, Stereoisomerism
Publication Number: 3709257
ISBN: 978-1-321-84836-6
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