Predicting the open conformations of protein kinases using molecular dynamics simulations

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dc.contributor.author Bjarnadottir, Una
dc.contributor.author Nielsen, Jens Erik
dc.date.accessioned 2011-10-14T14:28:23Z
dc.date.available 2011-10-14T14:28:23Z
dc.date.copyright 2011 Wiley Periodicals, Inc. en
dc.date.issued 2012-01
dc.identifier.citation Biopolymers en
dc.identifier.issn 1097-0282
dc.identifier.uri http://hdl.handle.net/10197/3230
dc.description.abstract Protein kinases (PK) control phosphorylation in eukaryotic cells, and thereby regulate metabolic pathways, cell cycle progression, apoptosis and transcription. Consequently there is significant interest in manipulating PK activity and treat diseases by using small-molecule drugs. All PK catalytic domains undergo large conformational changes as a result of substrate binding and phosphorylation. The “closed” state of a PK cataltic domain is the only state able to phosphorylate the target substrate, which makes the two other observed states (the “open” and the “intermediate” states) interesting drug targets. We investigate if MD simulations starting from the closed state of the catalytic domain of protein kinase A (C-PKA) can be used to produce realistic structures representing the intermediate and/or open conformation of C-PKA, since this would allow for drug docking calculations and drug design using MD snapshots. We perform 36 ten-nanosecond MD simulations starting from the closed conformation (PDB ID: 1ATP) of C-PKA in various liganded and phosphorylated states. The results show that MD simulations are capable of reproducing the open conformation of C-PKA with good accuracy within 1 ns of simulation as measured by Cα RMSDs and RMSDs of atoms defining the ATPbinding pocket. Importantly we are able to show that even without knowledge of the structure of the open form of C-PKA, we can identify the MD snapshots resembling the open conformation most using the open structure of a different protein kinase displaying only 23% sequence identity to C-PKA. en
dc.description.sponsorship Science Foundation Ireland en
dc.description.sponsorship Health Research Board en
dc.format.extent 1244382 bytes
dc.format.mimetype application/pdf
dc.language.iso en en
dc.publisher Wiley-Blackwell en
dc.relation.requires Conway Institute Research Collection en
dc.rights This is the pre-peer reviewed version of the following article: Bjarnadottir, U. and Nielsen, J. E. (2011), Predicting the open conformations of protein kinases using molecular dynamics simulations. Biopolymers. doi: 10.1002/bip.21704 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/bip.21704/abstract en
dc.subject Protein kinase en
dc.subject Activation process en
dc.subject Molecular dynamics simulations en
dc.subject Conformational change en
dc.subject Protein Dynamics en
dc.subject.lcsh Protein kinases en
dc.subject.lcsh Molecular dynamics en
dc.subject.lcsh Proteins--Conformation en
dc.subject.mesh Protein Kinases en
dc.subject.mesh Protein Conformation en
dc.subject.mesh Molecular Dynamics Simulation en
dc.title Predicting the open conformations of protein kinases using molecular dynamics simulations en
dc.title.alternative MD simulations of C-PKA en
dc.type Journal Article en
dc.internal.availability Full text available en
dc.internal.webversions Publisher's version en
dc.internal.webversions http://dx.doi.org/10.1002/bip.21704 en
dc.status Peer reviewed en
dc.identifier.volume 97 en
dc.identifier.issue 1 en
dc.identifier.startpage 65 en
dc.identifier.endpage 72 en
dc.identifier.doi 10.1002/bip.21704
dc.neeo.contributor Bjarnadottir|Una|aut| en
dc.neeo.contributor Nielsen|Jens Erik|aut| en
dc.description.admin ab,ke,SB-09/09/2011 en


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