title: Exploring protein kinase conformation using swarm-enhanced sampling molecular dynamics.
abstract: Protein plasticity, while often linked to biological function, also provides opportunities for rational design of selective and potent inhibitors of their function. The application of computational methods to the prediction of concealed protein concavities is challenging, as the motions involved can be significant and occur over long time scales. Here we introduce the swarm-enhanced sampling molecular dynamics (sesMD) method as a tool to improve sampling of conformational landscapes. In this approach, a swarm of replica simulations interact cooperatively via a set of pairwise potentials incorporating attractive and repulsive components. We apply the sesMD approach to explore the conformations of the DFG motif in the protein p38α mitogen-activated protein kinase. In contrast to multiple MD simulations, sesMD trajectories sample a range of DFG conformations, some of which map onto existing crystal structures. Simulated structures intermediate between the DFG-in and DFG-out conformations are predicted to have druggable pockets of interest for structure-based ligand design.
authors.affiliation: Manchester Pharmacy School, University of Manchester , Oxford Road, Manchester M13 9PT, U.K.
authors.forename: Alessio
authors.initials: A
authors.lastname: Atzori
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Bruce
authors.forename: Kepa K
authors.initials: KK
authors.lastname: Burusco
authors.forename: Berthold
authors.initials: B
authors.lastname: Wroblowski
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D020816:Amino Acid Motifs; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D012107:Research Design; D054852:Small Molecule Libraries / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D048308:Mitogen-Activated Protein Kinase 14