Molecules in motion: Computing structural flexibility

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dc.contributor.advisorKavraki, Lydia E.
dc.creatorShehu, Amarda
dc.date.accessioned2018-12-03T18:31:44Z
dc.date.available2018-12-03T18:31:44Z
dc.date.issued2008
dc.description.abstractGrowing databases of protein sequences in the post-genomic era call for computational methods to extract structure and function from a protein sequence. In flexible molecules like proteins, function cannot be reliably extracted from a few structures. The amino-acid chain assumes various spatial arrangements (conformations) to modulate biological function. Characterizing the flexibility of a protein under physiological (native) conditions remains an open problem in computational biology. This thesis addresses the problem of characterizing the native flexibility of a protein by computing conformations populated under native conditions. Such computation involves locating free-energy minima in a high-dimensional conformational space. The methods proposed in this thesis search for native conformations using systematically less information from experiment: first employing an experimental structure, then using only a closure constraint in cyclic cysteine-rich peptides, and finally employing only the amino-acid sequence of small- to medium-size proteins. A novel method is proposed to compute structural fluctuations of a protein around an experimental structure. The method combines a robotics-inspired exploration of the conformational space with a statistical mechanics formulation. Thermodynamic quantities measured over generated conformations reproduce experimental data of broad time scales on small (∼ 100 amino acids) proteins with non-concerted motions. Capturing concerted motions motivates the development of the next methods. A second method is proposed that employs a closure constraint to generate native conformations of cyclic cysteine-rich peptides. The method first explores the entire conformational space, then explores in present energy minima until no lower-energy minima emerge. The method captures relevant features of the native state also observed in experiment for 20–30 amino-acid long peptides. A final method is proposed that implements a similar exploration but for longer proteins and employing only amino-acid sequence. In its first stage, the method explores the entire conformational space at a coarse-grained level of detail. A second stage focuses the exploration to low-energy regions in more detail. All-atom conformational ensembles are obtained for proteins that populate various functional states through large-scale concerted motions. These ensembles capture well the populated functional states of proteins up to 214 amino-acids long.
dc.format.extent239 pp
dc.identifier.callnoTHESIS COMP.SCI. 2009 SHEHU
dc.identifier.citationShehu, Amarda. "Molecules in motion: Computing structural flexibility." (2008) Diss., Rice University. <a href="https://hdl.handle.net/1911/103599">https://hdl.handle.net/1911/103599</a>.
dc.identifier.digital304510187
dc.identifier.urihttps://hdl.handle.net/1911/103599
dc.language.isoeng
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.
dc.subjectBioinformatics
dc.subjectBiophysics
dc.subjectComputer science
dc.subjectApplied sciences
dc.subjectBiological sciences
dc.subjectEquilibrium ensemble
dc.subjectMultiscale exploration
dc.subjectNative state
dc.subjectProtein conformations
dc.subjectRobotics-inspired
dc.subjectStatistical mechanics
dc.titleMolecules in motion: Computing structural flexibility
dc.typeThesis
dc.type.materialText
thesis.degree.departmentComputer Science
thesis.degree.disciplineEngineering
thesis.degree.grantorRice University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
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