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10.1039/d0mo00103a http://scihub22266oqcxt.onion/10.1039/d0mo00103a 33174576!ä!33174576 Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 215.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 316.4 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 316.4 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Mol+Omics 2021 ; 17 (1): 86-94 Nephropedia Template TP {{tp|p=33174576|t=2021. Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout |pdf=|usr=}}{{33174576}} gab.com Text Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout JO: Mol Omics http://www.kidney.de/pget.php?&tw=1&pmid=33174576 #FOAvip Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an etiological agent of the current rapidly growing outbreak of coronavirus disease (COVID-19), which is straining health systems around the world. Disrupting the intermolecular association of SARS-CoV-2 spike glycoprotein (S protein) with its cell surface receptor human angiotensin-converting enzyme 2 (hACE2) has been recognized as a promising therapeutic strategy against COVID-19. The association is a typical peptide-mediated interaction, where the hACE adopts an alpha1-helix, which can form a two-helix bundle with the alpha2-helix, to pack against a flat pocket on the S protein surface. Here, we demonstrate that the protein context of full-length hACE plays an essential role in supporting the hACE2 alpha1-helix recognition by viral S protein. Energetic analysis reveals that the alpha1-helical peptide (alphaHP) and also the two-helix bundle peptide (tBP) cannot bind effectively to S protein when they are split from the hACE protein. The context contributes moderately and considerably to the direct readout (DR) and indirect readout (IR) of peptide recognition, respectively. Dynamics simulation suggests that the two free peptides exhibit a large intrinsic disorder without the support of protein context, which would incur a considerable entropy penalty upon binding to S protein. To restore the IR effect lost by splitting peptides from hACE, we herein propose employing hydrocarbon stapling and cyclization strategies to constrain the free alphaHP and tBP peptides into their native ordered conformations, respectively. The stapling and cyclization are carefully designed in order to avoid influencing the peptide DR effect, which has been demonstrated to improve the peptide binding affinity (but not specificity) to S protein. The stapling/cyclization-imposed conformational constraint can effectively minimize the unfavorable IR effect (i) by reducing the peptide flexibility and entropy cost upon their binding to S protein, and (ii) by helping peptide pre-folding into their native state to facilitate the conformational selection by S protein. Twit Text FOAVip Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout ????Mol Omics http://www.kidney.de/pget.php?&tw=1&pmid=33174576 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33174576 #FOAvip English Wikipedia <ref>{{Cite pmid|33174576}}</ref> Context contribution to the intermolecular recognition of human ACE2-derived peptides by SARS-CoV-2 spike protein: implications for improving the peptide affinity but not altering the peptide specificity by optimizing indirect readout #MMPMID33174576 Zhou P; Wang H; Chen Z; Liu Q Mol Omics 2021[Feb]; 17 (1): 86-94 PMID33174576show ga Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an etiological agent of the current rapidly growing outbreak of coronavirus disease (COVID-19), which is straining health systems around the world. Disrupting the intermolecular association of SARS-CoV-2 spike glycoprotein (S protein) with its cell surface receptor human angiotensin-converting enzyme 2 (hACE2) has been recognized as a promising therapeutic strategy against COVID-19. The association is a typical peptide-mediated interaction, where the hACE adopts an alpha1-helix, which can form a two-helix bundle with the alpha2-helix, to pack against a flat pocket on the S protein surface. Here, we demonstrate that the protein context of full-length hACE plays an essential role in supporting the hACE2 alpha1-helix recognition by viral S protein. Energetic analysis reveals that the alpha1-helical peptide (alphaHP) and also the two-helix bundle peptide (tBP) cannot bind effectively to S protein when they are split from the hACE protein. The context contributes moderately and considerably to the direct readout (DR) and indirect readout (IR) of peptide recognition, respectively. Dynamics simulation suggests that the two free peptides exhibit a large intrinsic disorder without the support of protein context, which would incur a considerable entropy penalty upon binding to S protein. To restore the IR effect lost by splitting peptides from hACE, we herein propose employing hydrocarbon stapling and cyclization strategies to constrain the free alphaHP and tBP peptides into their native ordered conformations, respectively. The stapling and cyclization are carefully designed in order to avoid influencing the peptide DR effect, which has been demonstrated to improve the peptide binding affinity (but not specificity) to S protein. The stapling/cyclization-imposed conformational constraint can effectively minimize the unfavorable IR effect (i) by reducing the peptide flexibility and entropy cost upon their binding to S protein, and (ii) by helping peptide pre-folding into their native state to facilitate the conformational selection by S protein. |Angiotensin-Converting Enzyme 2/*chemistry/*metabolism[MESH] |Binding Sites[MESH] |Coronavirus Infections/genetics/metabolism[MESH] |Humans[MESH] |Molecular Dynamics Simulation[MESH] |Peptides/chemistry/*metabolism[MESH] |Protein Binding[MESH] |Spike Glycoprotein, Coronavirus/genetics/*metabolism[MESH]Context contribution to the intermolecular recognition of human ACE2-d(epmc).pdf DeepDyve Pubget Overpricing