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dc.contributor.authorHenderson, Jack A
dc.contributor.authorVerma, Neha
dc.contributor.authorHarris, Robert C
dc.contributor.authorLiu, Ruibin
dc.contributor.authorShen, Jana
dc.date.accessioned2020-10-05T20:23:55Z
dc.date.available2020-10-05T20:23:55Z
dc.date.issued2020-09-21
dc.identifier.urihttp://hdl.handle.net/10713/13834
dc.description.abstractBroad-spectrum antiviral drugs are urgently needed to stop the Coronavirus Disease 2019 pandemic and prevent future ones. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is related to the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which have caused the previous outbreaks. The papain-like protease (PLpro) is an attractive drug target due to its essential roles in the viral life cycle. As a cysteine protease, PLpro is rich in cysteines and histidines, and their protonation/deprotonation modulates catalysis and conformational plasticity. Here, we report the pKa calculations and assessment of the proton-coupled conformational dynamics of SARS-CoV-2 in comparison to SARS-CoV and MERS-CoV PLpros using the recently developed graphical processing unit (GPU)-accelerated implicit-solvent continuous constant pH molecular dynamics method with a new asynchronous replica-exchange scheme, which allows computation on a single GPU card. The calculated pKa's support the catalytic roles of the Cys-His-Asp triad. We also found that several residues can switch protonation states at physiological pH among which is C270/271 located on the flexible blocking loop 2 (BL2) of SARS-CoV-2/CoV PLpro. Simulations revealed that the BL2 can open and close depending on the protonation state of C271/270, consistent with the most recent crystal structure evidence. Interestingly, despite the lack of an analogous cysteine, BL2 in MERS-CoV PLpro is also very flexible, challenging a current hypothesis. These findings are supported by the all-atom fixed-charge simulations and provide a starting point for more detailed studies to assist the structure-based design of broad-spectrum inhibitors against CoV PLpros.en_US
dc.description.urihttps://doi.org/10.1063/5.0020458en_US
dc.language.isoenen_US
dc.publisherAmerican Institute of Physicsen_US
dc.relation.ispartofThe Journal of chemical physicsen_US
dc.subjectbroad-spectrum antiviral drugsen_US
dc.subject.meshCOVID-19en_US
dc.subject.meshAntiviral Agentsen_US
dc.subject.meshSARS-CoV-2en_US
dc.subject.meshSARS Virusen_US
dc.subject.meshMiddle East Respiratory Syndrome Coronavirusen_US
dc.subject.meshCoronavirus Papain-Like Proteasesen_US
dc.titleAssessment of proton-coupled conformational dynamics of SARS and MERS coronavirus papain-like proteases: Implication for designing broad-spectrum antiviral inhibitors.en_US
dc.typeArticleen_US
dc.identifier.doi10.1063/5.0020458
dc.identifier.pmid32962355
dc.source.volume153
dc.source.issue11
dc.source.beginpage115101
dc.source.endpage
dc.source.countryUnited States


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