Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive Inhibitors
Binary (nucleotide-protein dimer and hexamer complexes) and ternary (nucleotide-protein-inhibitor complexes) p97 complexes were subjected to molecular dynamics simulations in an attempt to further our understanding of the p97 protein oligomer domain stability and, more importantly, of the recently r...
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2019-06-01
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doaj-fc209389477f416ca78d5359ab5a0e912020-11-25T01:55:04ZengSlovenian Chemical SocietyActa Chimica Slovenica1318-02071580-31552019-06-0166239540110.17344/acsi.2019.4880693Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive InhibitorsStefano Rendine0Christian Orrenius1Federico Dapiaggi2Stefano Pieraccini3Ilaria Motto4Roberto D'Alessio5Paola Magnaghi6Antonella Isacchi7Eduard Felder8Maurizio Sironi9Syngenta Crop Protection AG, Crop Protection Research, Schaffhauserstrasse, CH-4332 Stein, SwitzerlandNerviano Medical SciencesUniversità degli studi di MilanoUniversità degli studi di MilanoNerviano Medical SciencesNerviano Medical SciencesNerviano Medical SciencesNerviano Medical SciencesNerviano Medical SciencesUniveristà degli Studi di MilanoBinary (nucleotide-protein dimer and hexamer complexes) and ternary (nucleotide-protein-inhibitor complexes) p97 complexes were subjected to molecular dynamics simulations in an attempt to further our understanding of the p97 protein oligomer domain stability and, more importantly, of the recently reported diverse molecular mechanisms of inhibition including allosteric, ATP-competitive and covalent inhibitors. Analysis of stable states following equilibration phases indicated a higher intrinsic stability of the homohexamer as opposed to the dimer, and of N-D1 domains as opposed to the D2 domain. The molecular dynamics of the proposed allosteric binding model reproduced important molecular interactions identified experimentally with high frequency throughout the trajectory. Observed conformational changes occurring in the D2 nucleotide binding site provided a novel bind-rearrange-react hypothesis of stepwise molecular events involved in the specific covalent inhibitor mode of action.https://journals.matheo.si/index.php/ACSi/article/view/4880Drug designprotein protein interactionsmm-pbsamolecular dynamics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stefano Rendine Christian Orrenius Federico Dapiaggi Stefano Pieraccini Ilaria Motto Roberto D'Alessio Paola Magnaghi Antonella Isacchi Eduard Felder Maurizio Sironi |
spellingShingle |
Stefano Rendine Christian Orrenius Federico Dapiaggi Stefano Pieraccini Ilaria Motto Roberto D'Alessio Paola Magnaghi Antonella Isacchi Eduard Felder Maurizio Sironi Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive Inhibitors Acta Chimica Slovenica Drug design protein protein interactions mm-pbsa molecular dynamics |
author_facet |
Stefano Rendine Christian Orrenius Federico Dapiaggi Stefano Pieraccini Ilaria Motto Roberto D'Alessio Paola Magnaghi Antonella Isacchi Eduard Felder Maurizio Sironi |
author_sort |
Stefano Rendine |
title |
Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive Inhibitors |
title_short |
Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive Inhibitors |
title_full |
Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive Inhibitors |
title_fullStr |
Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive Inhibitors |
title_full_unstemmed |
Molecular Dynamics Simulations of p97 Including Covalent, Allosteric and ATP-competitive Inhibitors |
title_sort |
molecular dynamics simulations of p97 including covalent, allosteric and atp-competitive inhibitors |
publisher |
Slovenian Chemical Society |
series |
Acta Chimica Slovenica |
issn |
1318-0207 1580-3155 |
publishDate |
2019-06-01 |
description |
Binary (nucleotide-protein dimer and hexamer complexes) and ternary (nucleotide-protein-inhibitor complexes) p97 complexes were subjected to molecular dynamics simulations in an attempt to further our understanding of the p97 protein oligomer domain stability and, more importantly, of the recently reported diverse molecular mechanisms of inhibition including allosteric, ATP-competitive and covalent inhibitors. Analysis of stable states following equilibration phases indicated a higher intrinsic stability of the homohexamer as opposed to the dimer, and of N-D1 domains as opposed to the D2 domain. The molecular dynamics of the proposed allosteric binding model reproduced important molecular interactions identified experimentally with high frequency throughout the trajectory. Observed conformational changes occurring in the D2 nucleotide binding site provided a novel bind-rearrange-react hypothesis of stepwise molecular events involved in the specific covalent inhibitor mode of action. |
topic |
Drug design protein protein interactions mm-pbsa molecular dynamics |
url |
https://journals.matheo.si/index.php/ACSi/article/view/4880 |
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