Delineating Structural Characteristics of Viral Capsid Proteins Critical for Their Functional Assembly.
dc.contributor.author | Cheng, Shanshan | en_US |
dc.date.accessioned | 2015-01-30T20:11:24Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2015-01-30T20:11:24Z | |
dc.date.issued | 2014 | en_US |
dc.date.submitted | 2014 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/110375 | |
dc.description.abstract | Viral capsids exhibit elaborate and symmetrical architectures of defined sizes and remarkable mechanical properties not seen with cellular macromolecular complexes. The limited coding capacity of viral genome necessitates economization upon one or a few identical gene products known as capsid proteins for shell assembly. The functional uniqueness of this class of proteins prompts questions on structural features critically important for their higher order organization. In this thesis, I develop the statistical framework and computational tools to pinpoint the structural characteristics of viral capsid proteins exclusive to the virosphere by testing a series of hypotheses, providing understanding of the physical principles governing molecular self-association that can inform rational design of nanomaterials and therapeutics. In the first chapter, I compare the folds of capsid proteins with those of generic proteins, and establish that capsid proteins are segregated in structural fold space, highlighting the geometric constraints of these building blocks for tiling into a closed shell. Second, I develop a software program, PCalign, for quantifying the physicochemical similarity between protein-protein interfaces. This tool overcomes the major limitation of current methods by using a reduced representation of structural information, greatly expanding the structural interface space that can be investigated through inclusion of large macromolecular assemblies that are often not amenable to high resolution experimental techniques. As an application of this method, I propose a computational framework for template-based protein inhibitor design, leading to the prediction of putative binders for a therapeutic target, the influenza hemagglutinin. In silico evaluations of these candidate drugs parallel those of known protein binders, offering great promise in expanding therapeutic options in the clinic. Lastly, I examine protein-protein interfaces using PCalign, and find strong statistical evidence for the disconnectivity between capsid proteins and cellular proteins in structural interface space. I thus conclude that the basic shape and the sticky edges of these Lego pieces act concertedly to create the sophisticated shell architecture. In summary, the novel tools contributed by this dissertation work lead to delineation of structural features of viral capsid proteins that make them functionally unique, providing an understanding that will serve as the basis for prediction and design. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Viral capsid proteins | en_US |
dc.subject | Structural bioinformatics | en_US |
dc.title | Delineating Structural Characteristics of Viral Capsid Proteins Critical for Their Functional Assembly. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Bioinformatics | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Brooks Iii, Charles L. | en_US |
dc.contributor.committeemember | Smith, Janet | en_US |
dc.contributor.committeemember | Grant, Barry | en_US |
dc.contributor.committeemember | Shedden, Kerby A. | en_US |
dc.contributor.committeemember | Zhang, Yang | en_US |
dc.subject.hlbsecondlevel | Science (General) | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/110375/1/sscheng_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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