Browsing by Author "Lambeth, Bradley"

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    Multiscale Approach to the Determination of the Photoactive Yellow Protein Signaling State Ensemble
    (Public Library of Science, 2014) Rohrdanz, Mary A.; Zheng, Wenwei; Lambeth, Bradley; Vreede, Jocelyne; Clementi, Cecilia; Center for Theoretical Biological Physics
    The nature of the optical cycle of photoactive yellow protein (PYP) makes its elucidation challenging for both experiment and theory. The long transition times render conventional simulation methods ineffective, and yet the short signaling-state lifetime makes experimental data difficult to obtain and interpret. Here, through an innovative combination of computational methods, a prediction and analysis of the biological signaling state of PYP is presented. Coarse-grained modeling and locally scaled diffusion map are first used to obtain a rough bird's-eye view of the free energy landscape of photo-activated PYP. Then all-atom reconstruction, followed by an enhanced sampling scheme; diffusion map-directed-molecular dynamics are used to focus in on the signaling-state region of configuration space and obtain an ensemble of signaling state structures. To the best of our knowledge, this is the first time an all-atom reconstruction from a coarse grained model has been performed in a relatively unexplored region of molecular configuration space. We compare our signaling state prediction with previous computational and more recent experimental results, and the comparison is favorable, which validates the method presented. This approach provides additional insight to understand the PYP photo cycle, and can be applied to other systems for which more direct methods are impractical.
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    Towards Adaptive Resolution Modeling of Biomolecular Systems in their Environment
    (2012-09-05) Lambeth, Bradley; Clementi, Cecilia; Pasquali, Matteo; Scuseria, Gustavo E.
    Water plays a critical role in the function and structure of biological systems. Current techniques to study biologically relevant events that span many length and time scales are limited by the prohibitive computational cost of including accurate effects from the aqueous environment. The aim of this work is to expand the reach of current molecular dynamics techniques by reducing the computational cost for achieving an accurate description of water and its effects on biomolecular systems. This work builds from the assumption that the “local” effect of water (e.g. the local orientational preferences and hydrogen bonding) can be effectively modelled considering only the atomistic detail in a very limited region. A recent adaptive resolution simulation technique (AdResS) has been developed to practically apply this idea; in this work it will be extended to systems of simple hydrophobic solutes to determine a characteristic length for which thermodynamic, structural, and dynamic properties are preserved near the solute. This characteristic length can then be used for simulation of biomolecular systems, specifically those involving protein dynamics in water. Before this can be done, current coarse grain models must be adapted to couple with a coarse grain model of water. This thesis is organized in to five chapters. The first will give an overview of water, and the current methodologies used to simulate water in biological systems. The second chapter will describe the AdResS technique and its application to simple test systems. The third chapter will show that this method can be used to accurately describe hydrophobic solutes in water. The fourth chapter describes the use of coarse grain models as a starting point for targeted search with all-atom models. The final chapter will describe attempts to couple a coarse grain model of a protein with a single-site model for water, and it’s implications for future multi-resolution studies.