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10.1021/acs.jpclett.1c00425 http://scihub22266oqcxt.onion/10.1021/acs.jpclett.1c00425 33900080!8097931!33900080     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Phys+Chem+Lett 2021 ; 12 (17): 4195-4202 Nephropedia Template TP {{tp|p=33900080|t=2021. Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design |pdf=|usr=}}{{33900080}} gab.com Text Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design JO: J Phys Chem Lett http://www.kidney.de/pget.php?&tw=1&pmid=33900080 #FOAvip The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the alpha-ketoamide 13b. We show that with the inhibitors the free energy cost to reach the charge-separated state of the active-site dyad is lower, with N3 inducing the most significant reduction. We also show that a few key sites (including specific water molecules) significantly enhance or reduce the thermodynamic feasibility of the PT reaction, with selective desolvation of the active site playing a crucial role. The approach presented is a cost-effective procedure to identify the enzyme regions that control the activation of the catalytic reaction and is thus also useful to guide the design of inhibitors. Twit Text FOAVip Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design ????J Phys Chem Lett http://www.kidney.de/pget.php?&tw=1&pmid=33900080 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33900080 #FOAvip English Wikipedia <ref>{{Cite pmid|33900080}}</ref> Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design #MMPMID33900080 Zanetti-Polzi L; Smith MD; Chipot C; Gumbart JC; Lynch DL; Pavlova A; Smith JC; Daidone I J Phys Chem Lett 2021[May]; 12 (17): 4195-4202 PMID33900080show ga The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the alpha-ketoamide 13b. We show that with the inhibitors the free energy cost to reach the charge-separated state of the active-site dyad is lower, with N3 inducing the most significant reduction. We also show that a few key sites (including specific water molecules) significantly enhance or reduce the thermodynamic feasibility of the PT reaction, with selective desolvation of the active site playing a crucial role. The approach presented is a cost-effective procedure to identify the enzyme regions that control the activation of the catalytic reaction and is thus also useful to guide the design of inhibitors. |*Drug Design[MESH] |Antiviral Agents/chemistry/metabolism[MESH] |Biocatalysis[MESH] |COVID-19/pathology/virology[MESH] |Catalytic Domain[MESH] |Humans[MESH] |Molecular Dynamics Simulation[MESH] |Protease Inhibitors/*chemistry/metabolism[MESH] |Protons[MESH] |Quantum Theory[MESH] |SARS-CoV-2/*enzymology/isolation & purification[MESH] |Thermodynamics[MESH]Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Imp(epmc).pdf DeepDyve Pubget Overpricing