Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation.

2.50
Hdl Handle:
http://hdl.handle.net/10547/227191
Title:
Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation.
Authors:
Huggins, David J.; McKenzie, Grahame J.; Robinson, Daniel D.; Narváez, Ana J.; Hardwick, Bryn; Roberts-Thomson, Meredith; Venkitaraman, Ashok R.; Grant, Guy H.; Payne, Mike C.
Abstract:
The Polo-Like Kinase 1 (PLK1) acts as a central regulator of mitosis and is over-expressed in a wide range of human tumours where high levels of expression correlate with a poor prognosis. PLK1 comprises two structural elements, a kinase domain and a polo-box domain (PBD). The PBD binds phosphorylated substrates to control substrate phosphorylation by the kinase domain. Although the PBD preferentially binds to phosphopeptides, it has a relatively broad sequence specificity in comparison with other phosphopeptide binding domains. We analysed the molecular determinants of recognition by performing molecular dynamics simulations of the PBD with one of its natural substrates, CDC25c. Predicted binding free energies were calculated using a molecular mechanics, Poisson-Boltzmann surface area approach. We calculated the per-residue contributions to the binding free energy change, showing that the phosphothreonine residue and the mainchain account for the vast majority of the interaction energy. This explains the very broad sequence specificity with respect to other sidechain residues. Finally, we considered the key role of bridging water molecules at the binding interface. We employed inhomogeneous fluid solvation theory to consider the free energy of water molecules on the protein surface with respect to bulk water molecules. Such an analysis highlights binding hotspots created by elimination of water molecules from hydrophobic surfaces. It also predicts that a number of water molecules are stabilized by the presence of the charged phosphate group, and that this will have a significant effect on the binding affinity. Our findings suggest a molecular rationale for the promiscuous binding of the PBD and highlight a role for bridging water molecules at the interface. We expect that this method of analysis will be very useful for probing other protein surfaces to identify binding hotspots for natural binding partners and small molecule inhibitors.
Affiliation:
TCM Group, Cavendish Laboratory, University of Cambridge
Citation:
Computational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation. 2010, 6 (8): PLoS Comput. Biol.
Journal:
PLoS computational biology
Issue Date:
12-Aug-2010
URI:
http://hdl.handle.net/10547/227191
DOI:
10.1371/journal.pcbi.1000880
PubMed ID:
20711360
Type:
Article
Language:
en
ISSN:
1553-7358
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorHuggins, David J.en_GB
dc.contributor.authorMcKenzie, Grahame J.en_GB
dc.contributor.authorRobinson, Daniel D.en_GB
dc.contributor.authorNarváez, Ana J.en_GB
dc.contributor.authorHardwick, Brynen_GB
dc.contributor.authorRoberts-Thomson, Meredithen_GB
dc.contributor.authorVenkitaraman, Ashok R.en_GB
dc.contributor.authorGrant, Guy H.en_GB
dc.contributor.authorPayne, Mike C.en_GB
dc.date.accessioned2012-06-01T13:57:55Z-
dc.date.available2012-06-01T13:57:55Z-
dc.date.issued2010-08-12-
dc.identifier.citationComputational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation. 2010, 6 (8): PLoS Comput. Biol.en_GB
dc.identifier.issn1553-7358-
dc.identifier.pmid20711360-
dc.identifier.doi10.1371/journal.pcbi.1000880-
dc.identifier.urihttp://hdl.handle.net/10547/227191-
dc.description.abstractThe Polo-Like Kinase 1 (PLK1) acts as a central regulator of mitosis and is over-expressed in a wide range of human tumours where high levels of expression correlate with a poor prognosis. PLK1 comprises two structural elements, a kinase domain and a polo-box domain (PBD). The PBD binds phosphorylated substrates to control substrate phosphorylation by the kinase domain. Although the PBD preferentially binds to phosphopeptides, it has a relatively broad sequence specificity in comparison with other phosphopeptide binding domains. We analysed the molecular determinants of recognition by performing molecular dynamics simulations of the PBD with one of its natural substrates, CDC25c. Predicted binding free energies were calculated using a molecular mechanics, Poisson-Boltzmann surface area approach. We calculated the per-residue contributions to the binding free energy change, showing that the phosphothreonine residue and the mainchain account for the vast majority of the interaction energy. This explains the very broad sequence specificity with respect to other sidechain residues. Finally, we considered the key role of bridging water molecules at the binding interface. We employed inhomogeneous fluid solvation theory to consider the free energy of water molecules on the protein surface with respect to bulk water molecules. Such an analysis highlights binding hotspots created by elimination of water molecules from hydrophobic surfaces. It also predicts that a number of water molecules are stabilized by the presence of the charged phosphate group, and that this will have a significant effect on the binding affinity. Our findings suggest a molecular rationale for the promiscuous binding of the PBD and highlight a role for bridging water molecules at the interface. We expect that this method of analysis will be very useful for probing other protein surfaces to identify binding hotspots for natural binding partners and small molecule inhibitors.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PLoS computational biologyen_GB
dc.subject.meshBinding Sites-
dc.subject.meshCell Cycle Proteins-
dc.subject.meshHumans-
dc.subject.meshMolecular Dynamics Simulation-
dc.subject.meshPhosphopeptides-
dc.subject.meshPhosphorylation-
dc.subject.meshPhosphothreonine-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Interaction Domains and Motifs-
dc.subject.meshProtein-Serine-Threonine Kinases-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshSubstrate Specificity-
dc.subject.meshcdc25 Phosphatases-
dc.titleComputational analysis of phosphopeptide binding to the polo-box domain of the mitotic kinase PLK1 using molecular dynamics simulation.en
dc.typeArticleen
dc.contributor.departmentTCM Group, Cavendish Laboratory, University of Cambridgeen_GB
dc.identifier.journalPLoS computational biologyen_GB

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