Journal Article


Jens Erik Nielsen
Una Bjarnadottir



protein conformation molecular dynamics simulations conformational change activation process protein kinases molecular dynamics protein kinase protein dynamics proteins conformation molecular dynamics simulation

Predicting the open conformations of protein kinases using molecular dynamics simulations (2012)

Abstract Protein kinases (PK) control phosphorylation in eukaryotic cells, and thereby regulatemetabolic pathways, cell cycle progression, apoptosis and transcription.Consequently there is significant interest in manipulating PK activity and treatdiseases by using small-molecule drugs. All PK catalytic domains undergo largeconformational 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 targetsubstrate, which makes the two other observed states (the “open” and the“intermediate” states) interesting drug targets. We investigate if MD simulationsstarting from the closed state of the catalytic domain of protein kinase A (C-PKA) canbe used to produce realistic structures representing the intermediate and/or openconformation of C-PKA, since this would allow for drug docking calculations and drug design using MD snapshots. We perform 36 ten-nanosecond MD simulationsstarting from the closed conformation (PDB ID: 1ATP) of C-PKA in various ligandedand phosphorylated states. The results show that MD simulations are capable ofreproducing the open conformation of C-PKA with good accuracy within 1 ns ofsimulation as measured by Cα RMSDs and RMSDs of atoms defining the ATPbindingpocket. Importantly we are able to show that even without knowledge of thestructure of the open form of C-PKA, we can identify the MD snapshots resemblingthe open conformation most using the open structure of a different protein kinasedisplaying only 23% sequence identity to C-PKA.
Collections Ireland -> University College Dublin -> Biomolecular and Biomedical Science Research Collection
Ireland -> University College Dublin -> Institutes and Centres
Ireland -> University College Dublin -> Conway Institute Research Collection
Ireland -> University College Dublin -> College of Science
Ireland -> University College Dublin -> Conway Institute
Ireland -> University College Dublin -> School of Biomolecular & Biomedical Science

Full list of authors on original publication

Jens Erik Nielsen, Una Bjarnadottir

Experts in our system

Jens Erik Nielsen
University College Dublin
Total Publications: 27