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dc.contributor.advisorDaniel Bolonen_US
dc.contributor.authorSamant, Neha S.
dc.date.accessioned2023-02-24T14:29:34Z
dc.date.available2023-02-24T14:29:34Z
dc.date.issued2023-01-24
dc.identifier.doi10.13028/bfwf-3a16en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51719
dc.description.abstractInteraction of mutations is ubiquitous in understanding protein fitness landscapes. Fitness landscapes are critical in understanding protein evolution and drug resistance. I aim to elucidate functional consequences of mutations in viral proteins. Retroviral proteases cleave highly diverse substrates, for example, HIV-1 protease (PR) cleaves dramatically different cleavage sites, making it a challenging and interesting system to investigate epistasis. Epistasis also plays an important role in shaping the emergence and evolution of drug resistance, for example in Oseltamivir resistance in Influenza A virus (IAV). To systematically investigate interaction of mutations in important proteins of RNA viruses, we used a mutational scanning approach, EMPIRIC, to investigate the fitness landscape of cleavage sites of HIV-1 PR. We observed that the cleavage sites had higher preferences for hydrophobic and aromatic amino acids. We also observed that negatively charged amino acids are preferred at positions distal to the scissile bond, where these positions are not involved in binding in the PR active site. Studying the fitness landscapes revealed that biophysical features and context-dependencies both mediate cutting of the cleavage sites. However, in-depth analysis of long-range and short-range contextuality would provide further insights on functional determinants of PR cleavage. I also explored the interaction of mutations in the neuraminidase (NA) of influenza A virus in response to inhibitor oseltamivir and identified positive epistasis between drug resistant mutation and a permissive mutation. Our data revealed the potential of epistasis in the evolution of drug resistance in circulating viruses. In summary, these studies provide a framework to examine evolutionary constraints and biochemical mechanisms of viral proteins that can contribute to the evolution of drug resistance.en_US
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2023 Samanten_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/en_US
dc.subjectFitness landscapeen_US
dc.subjectHIVen_US
dc.subjectIAVen_US
dc.subjectFACSen_US
dc.subjectNext-generation sequencingen_US
dc.subjectEMPIRICen_US
dc.subjectsaturation mutagenesisen_US
dc.subjectcleavage sitesen_US
dc.subjectHIV-1 Proteaseen_US
dc.titleInvestigating the role of mutational interdependencies on viral protein function and the evolution of drug resistanceen_US
dc.typeDoctoral Dissertationen_US
refterms.dateFOA2023-02-24T14:29:34Z
atmire.contributor.authoremailneha.samant@umassmed.eduen_US
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.description.thesisprogramInterdisciplinaryen_US
dc.identifier.orcid0000-0002-9514-0705en_US


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