Show simple item record

dc.contributor.authorQuaytman Machleder, Sara
dc.date.accessioned2018-07-12T17:35:37Z
dc.date.available2018-07-12T17:35:37Z
dc.date.issued2009
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2130.;Advisors: Steven D. Schwartz.
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:3357322
dc.identifier.urihttps://hdl.handle.net/20.500.12202/1045
dc.description.abstractThough enzymes have been studied for many years, there is still great controversy about the mechanism by which they accomplish rate enhancement. One current area of intense research is the proposition that the protein backbone of some enzymes contribute to the catalytic effect through couplings of the protein dynamics to chemistry. This would involve the coupling of fast motions---picosecond timescale vibrations---to the chemical step of the enzyme. Transition path sampling (TPS) is a well-known technique that generates reactive paths ensembles. Due to the atomic detail of these reactive paths, information about chemical mechanisms can be obtained. Application of the TPS method revealed the importance of fast vibrational motions for two isoforms of Lactate Dehydrogenase (human heart LDH and Bacillus stearothermophilus LDH) and human nucleoside phosphorylase (PNP). In each of these enzymes vibrational motions demonstrate to be integral parts of the reaction coordinate and assist in forming the transition state. For Lactate Dehydrogenase, important residues behind the active site were implicated in a compressional motion that brought the donor-acceptor atoms of the hydride closer together. In addition, residues behind the active site were implicated in a relaxational motion, locking the substrate in product formation. Using committor distribution analysis, these residue motions were proven as part of the reaction coordinate. By comparing the transition path ensembles of two homologs of LDH, small differences in the active site were found to reverse the order of the particle transfer of the chemical step. Whereas the hydride transfer preceded the proton transfer in the human heart LDH, the order is reversed in the Bacillus stearothermophilus homolog (in the direction of pyruvate to lactate). By applying the TPS to PNP, dynamic contributions were also found to assist in the transition state formation. A ribosidic bond is polarized by compression of the oxygen stack due to motions of the protein. The ribocation forms along with the departure of the hypoxanthine leaving group. The oxygen stack relaxes once the ribocation transition state is formed.
dc.publisherProQuest Dissertations & Theses
dc.subjectBiophysics.
dc.subjectChemistry.
dc.titleThe role of sub-picosecond dynamics in enzyme catalysis explored through transition path sampling
dc.typeDissertation


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record