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Protein structure and folding: An evolutionary perspective.

dc.contributor.authorGovindarajan, Sridhar
dc.contributor.advisorGoldstein, Richard A.
dc.date.accessioned2016-08-30T17:37:22Z
dc.date.available2016-08-30T17:37:22Z
dc.date.issued1997
dc.identifier.urihttp://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9825229
dc.identifier.urihttps://hdl.handle.net/2027.42/130970
dc.description.abstractProteins emerged from the evolutionary process shaped by natural selection. Insights into the evolutionary process can lead to a better understanding of the properties of these evolving molecules. Conversely consideration of the properties of proteins which constraints their evolution can provide an understanding of the principles and dynamics behind molecular evolution. This motivates our approach to understand protein structure, folding and evolution in an integrated fashion. Proteins under native physiological conditions fold to a native biologically-active state. During evolution, the effective interactions among residues in a protein can be adjusted through mutations to allow the protein to fold into its native structure on an adequate time-scale. We use simple lattice model proteins to explicitly deal with the complex nature of the protein folding process. Using exhaustive enumeration of the compact conformations of short proteins confined to these simple lattices, we find that the best structures for optimal folding are those that contain contacts rare in random structures, indicating the importance of non-local contacts along the sequence for assisting the folding process. Lattice models of proteins were used to examine the role of local propensities in stabilizing the native state of a protein. We find that contributions from the local propensities of individual residues in the protein to the stability of the native state of the protein are small under optimal folding conditions. We developed the concept of protein evolution on a foldability-fitness landscape. By considering the requirements imposed on proteins by their need to fold rapidly, and the ease with which such requirements can be fulfilled as a function of the native structure, we can explain why certain structures are repeatedly observed among proteins with negligible sequence similarity. We model the molecular evolution of simple lattice proteins as a walk in the fitness landscape, with the selective pressure explicitly included in the model. Evolving proteins marginally fulfill the selective criteria of foldability, suggesting why proteins are marginally stable. As the selective pressure is increased, evolutionary trajectories become increasingly confined to neutral networks where the sequence and the interactions can be significantly changed while a constant structure is maintained, explaining the observed plasticity in the sequence and robustness in the structure of proteins. The optimizability of the corresponding native structure has a strong effect on the size of these neutral networks, and thus on the nature of the evolutionary process. Finally we test the thermodynamic hypothesis for protein folding, which forms the basis of most theoretical work in understanding protein folding. We find that the probability of violating the hypothesis for a typical protein is extremely small as long as the protein explores more than a minuscule fraction of the conformation space.
dc.format.extent83 p.
dc.languageEnglish
dc.language.isoEN
dc.subjectEvolutionary
dc.subjectFitness Landscapes
dc.subjectMolecular Evolution
dc.subjectPerspective
dc.subjectProtein Folding
dc.subjectStructure
dc.titleProtein structure and folding: An evolutionary perspective.
dc.typeThesis
dc.description.thesisdegreenamePhDen_US
dc.description.thesisdegreedisciplineBiological Sciences
dc.description.thesisdegreedisciplineBiophysics
dc.description.thesisdegreedisciplineMolecular biology
dc.description.thesisdegreedisciplinePhysical chemistry
dc.description.thesisdegreedisciplinePure Sciences
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studies
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/130970/2/9825229.pdf
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


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