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dc.contributor.authorPatterson, John
dc.contributor.authorTsilimigras, Matthew C. B.
dc.contributor.authorLivesay, Dennis R.
dc.contributor.authorJacobs, Donald J.
dc.date.accessioned2019-04-10T21:44:31Z
dc.date.available2019-04-10T21:44:31Z
dc.date.issued2019-02-15
dc.identifier.citationPatterson, John; Tsilimigras, Matthew C. B.; Livesay, Dennis R.; Jacobs, Donald J. 2019. Evolution of stability/flexibility relationships in beta-lactamase. Biophysical Journal, vol. 116:no. 3:S1:pp 472aen_US
dc.identifier.issn0006-3495
dc.identifier.otherWOS:000460779802369
dc.identifier.urihttps://doi.org/10.1016/j.bpj.2018.11.2548
dc.identifier.urihttp://hdl.handle.net/10057/16007
dc.descriptionClick on the DOI link to access the article (may not be free).en_US
dc.description.abstractWe have curated over 100 structures of class A beta-lactamase proteins, a family of enzymes that is responsible for a considerable percentage of multidrug antibiotic resistance in bacteria. Our dataset includes three ancestral reconstructions of pre-hominid beta-lactamase structures unperturbed by modern day selective pressures on antibiotic resistance. Having ancient to extant protein structures represented, we sweep over the feature space governing thermodynamic stability to identify underlying cooperativity motifs that are conserved over the evolution of this protein family. Across all proteins within our dataset, mechanical cooperativity is analyzed by a minimum Distance Constraint Model in a similar fashion to previous work [1] to obtain quantitative stability/flexibility relationships (QSFR). We create an innovative thermodynamic landscape that describes the variance in thermodynamic stability across this family of proteins based upon a model parameter space that is relevant to enzyme activity. Using clustering and machine learning techniques, we identify relevant chemo-physical constraints that each beta-lactamase structure places on function and mechanical cooperativity over a diverse range of thermodynamic conditions. Under appropriate stability conditions for functionality, we aim to elucidate why antibiotic resistance differs between members in this class, despite all members sharing similar functional sites, global dynamics, and overall structural similarity. We also take into consideration the known pharmacological metadasta for each of these proteins to better understand the binding mechanisms between these enzymes and their various substrates. Our bioinformatics approach is designed to give insight into selective pressure and possible hidden mechanisms behind substrate selectivity in modern day beta-lactamases, while revealing the relevant evolutionary factors that guide ligand selectivity to change.en_US
dc.language.isoen_USen_US
dc.publisherCell Pressen_US
dc.relation.ispartofseriesBiophysical Journal;v.116:no.3
dc.subjectMeeting abstracten_US
dc.titleEvolution of stability/flexibility relationships in beta-lactamaseen_US
dc.typeAbstracten_US
dc.typeAnimationen_US
dc.typeArticleen_US
dc.rights.holder© 2019, Elsevieren_US


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