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Computational Studies of Stability, Dynamics, and Water Sorption Behavior of Proteins at Extreme Conditions

Speaker: Sang Beom Kim
Series: Final Public Oral Examinations
Location: Lapidus Lounge (E-Quad A210)
Date/Time: Wednesday, May 10, 2017, 3:30 p.m. - 5:00 p.m.

The main challenge in formulating biological therapeutics is to have proteins fully regain their native structures and functionalities after exposure to conditions such as low temperatures and extreme states of dehydration during lyophilization. This dissertation describes computational investigations of proteins at such extreme conditions, with specific focuses on understanding water sorption behaviors, low-temperature stability and dynamics, and folding/unfolding mechanism of proteins. We use advanced molecular-simulation and data-analysis techniques to obtain microscopic understanding of protein-water interactions at low temperature and dehydrated conditions. First, we present a novel computational technique we developed to investigate water sorption behaviors of amorphous protein matrices at dehydrated conditions. Using this technique, we make qualitative and quantitative comparisons of water sorption isotherms of amorphous protein matrices with varying degrees of underlying disorder. We also investigate the microscopic origin of hysteresis between the adsorption and desorption branches by explicitly comparing localized protein-water interactions in adsorption and desorption processes. We then present the effects of structural constraints on proteins on the water sorption isotherms, by modulating the disulfide linkages and backbone connectivity of the proteins. Second, low-temperature stability of proteins is investigated, which has broad implications for not only developing preservation strategies for biological materials but also understanding the evolution of freeze-tolerant organisms. Through extensive replica-exchange molecular dynamics simulations of Trp-cage miniprotein, we highlight the localized changes in protein structure upon cold denaturation. Moreover, we identified two distinct temperatures where low-temperature transitions in protein dynamics occur at varying levels of hydration. The contrasting temperature-dependent behaviors between hydrophilic and hydrophobic amino acids are explicitly analyzed in relation to the dynamical transitions. Finally, we illustrate that implementation of diffusion maps, a nonlinear dimensionality reduction technique, allows systematic parameterization of the low-dimensional description and unambiguous visualization of the protein folding pathways.