Examining the role of water and hydrophobicity in folding, aggregation, and allostery

Simple item page
dc.contributor.advisorMatysiak, Silvinaen_US
dc.contributor.authorCuster, Gregory Scotten_US
dc.contributor.departmentBioengineeringen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2018-07-17T06:14:33Z
dc.date.available2018-07-17T06:14:33Z
dc.date.issued2018en_US
dc.description.abstractSolvation and hydrophobicity drive many critical processes in nature, playing an important role in the folding of proteins, aggregation of surfactants into micelles, and in the disorder to order transitions that occur in some allosteric proteins upon ligand binding. Understanding how solvation and hydrophobicity affect these processes at a molecular level is important to finding new ways to use these processes, but it can be difficult to characterize these molecular details using experimental methods. Molecular dynamics (MD) simulations have proven useful in exploring details and thermodynamic conditions inaccessible in experiment, as MD captures the time evolution of the system at a molecular level. The phenomena which can be studied with an MD simulation depend on the mathematical model employed. Atomistic models provide the most detail for a simulation, but due to the computational costs required are not typically used to study phenomena which require large systems and time scales greater than several μs. Coarse-grained (CG) models reduce the complexity of the system being studied, enabling the exploration of phenomena that occur at longer time scales. We have developed CG models to study protein folding and surfactant aggregation. Our CG surfactant model uses a three-body potential to account for hydrogen bonding without an explicit electrostatic potential, reducing the computational cost of the model. With our surfactant model we studied the stability of non-ionic micelles at extremes of temperature, capturing a window of thermal stability with destabilization of the micelles at both high and low temperatures. We observed changes in structure and solvation of the micelle at low temperatures, with a shift in enthalpy of solvation water providing the driving force for destabilization. Solvation and hydrophobicity are also critical in the folding and stability of proteins. With a modified version of our surfactant model we characterized the folding landscape of a designed sequence which folds to a helical bundle in water. We found two competing folded states which differ by rotation of a helix and trade between hydrophobic packing and solvation of protein's core. Changes in hydrophobic packing can also be involved in the disorder to order transitions that occur upon liganding binding in an allosteric protein, such as the E. Coli biotin ligase/repressor (BirA), in which ligand binding promotes dimerization. We have used atomistic simulations of BirA mutants in collaboration with an experimental group to identify structural changes, accompanied by changes in solvation, at both the dimer interface and ligand binding regions for distal mutations which impact the functionality of BirA.en_US
dc.identifierhttps://doi.org/10.13016/M2K931932
dc.identifier.urihttp://hdl.handle.net/1903/20977
dc.language.isoenen_US
dc.subject.pqcontrolledMolecular chemistryen_US
dc.subject.pqcontrolledMolecular physicsen_US
dc.subject.pquncontrolledallosteryen_US
dc.subject.pquncontrolledmicellizationen_US
dc.subject.pquncontrolledprotein foldingen_US
dc.subject.pquncontrolledsolvationen_US
dc.titleExamining the role of water and hydrophobicity in folding, aggregation, and allosteryen_US
dc.typeDissertationen_US

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Custer_umd_0117E_18967.pdf
Size:
81.66 MB
Format:
Adobe Portable Document Format
Download

Collections

UMD Theses and Dissertations
Fischell Department of Bioengineering Theses and Dissertations