Exploring Protein Kinase Conformation Using Swarm-Enhanced Sampling Molecular Dynamics

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.

[1]  Albert C. Pan,et al.  Finding transition pathways using the string method with swarms of trajectories. , 2008, The journal of physical chemistry. B.

[2]  R. Dror,et al.  A conserved protonation-dependent switch controls drug binding in the Abl kinase , 2009, Proceedings of the National Academy of Sciences.

[3]  David Ozonoff,et al.  Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble , 2008, Chemical biology & drug design.

[4]  Hao Wang,et al.  Active Site Pressurization: A New Tool for Structure-Guided Drug Design and Other Studies of Protein Flexibility , 2008, J. Chem. Inf. Model..

[5]  Andrew E. Torda,et al.  Local elevation: A method for improving the searching properties of molecular dynamics simulation , 1994, J. Comput. Aided Mol. Des..

[6]  A. Laio,et al.  Metadynamics: a method to simulate rare events and reconstruct the free energy in biophysics, chemistry and material science , 2008 .

[7]  Francesco L Gervasio,et al.  The different flexibility of c-Src and c-Abl kinases regulates the accessibility of a druggable inactive conformation. , 2012, Journal of the American Chemical Society.

[8]  Harald Schwalbe,et al.  NMR characterization of kinase p38 dynamics in free and ligand-bound forms. , 2006, Angewandte Chemie.

[9]  Michael Feig,et al.  MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology. , 2004, Journal of molecular graphics & modelling.

[10]  Peter A. Kollman,et al.  Use of Locally Enhanced Sampling in Free Energy Calculations: Testing and Application to the α → β Anomerization of Glucose , 1998 .

[11]  Michael Habeck,et al.  Inferential NMR/X-ray-based structure determination of a dibenzo[a,d]cycloheptenone inhibitor-p38α MAP kinase complex in solution. , 2012, Angewandte Chemie.

[12]  John Kuriyan,et al.  A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain , 2006, PLoS biology.

[13]  Adrian H Elcock,et al.  Computational sampling of a cryptic drug binding site in a protein receptor: explicit solvent molecular dynamics and inhibitor docking to p38 MAP kinase. , 2006, Journal of molecular biology.

[14]  N. Gray,et al.  Rational design of inhibitors that bind to inactive kinase conformations , 2006, Nature chemical biology.

[15]  Susan S. Taylor,et al.  Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism , 2006, Proceedings of the National Academy of Sciences.

[16]  Y. Sugita,et al.  Replica-exchange molecular dynamics method for protein folding , 1999 .

[17]  Michael R. Shirts,et al.  Mathematical analysis of coupled parallel simulations. , 2001, Physical review letters.

[18]  Hiroki Shirai,et al.  Use of Amino Acid Composition to Predict Ligand-Binding Sites , 2007, J. Chem. Inf. Model..

[19]  A. Cavalli,et al.  Protein conformational transitions: the closure mechanism of a kinase explored by atomistic simulations. , 2009, Journal of the American Chemical Society.

[20]  Ron Elber,et al.  Homology as a Tool in Optimization Problems: Structure Determination of 2D Heteropolymers , 1995 .

[21]  A. Laio,et al.  Escaping free-energy minima , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Wilfred F. van Gunsteren,et al.  SWARM-MD: Searching Conformational Space by Cooperative Molecular Dynamics , 1998 .

[23]  B. Berne,et al.  Replica exchange with solute scaling: a more efficient version of replica exchange with solute tempering (REST2). , 2011, The journal of physical chemistry. B.

[24]  H. Edelsbrunner,et al.  Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design , 1998, Protein science : a publication of the Protein Society.

[25]  Arthur J. Olson,et al.  p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses. , 2009, Journal of molecular biology.

[26]  J Andrew McCammon,et al.  Discovery of a novel binding trench in HIV integrase. , 2004, Journal of medicinal chemistry.

[27]  Collin M. Stultz,et al.  MCSS functionality maps for a flexible protein , 1999, Proteins.

[28]  V. Pande,et al.  Activation pathway of Src kinase reveals intermediate states as novel targets for drug design , 2014, Nature Communications.

[29]  Paul Bamborough,et al.  Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. , 2008, Bioorganic & medicinal chemistry letters.

[30]  Federico Filomia,et al.  Insights into MAPK p38alpha DFG flip mechanism by accelerated molecular dynamics. , 2010, Bioorganic & medicinal chemistry.

[31]  Jonathan W. Essex,et al.  Pocket-Space Maps To Identify Novel Binding-Site Conformations in Proteins , 2011, J. Chem. Inf. Model..

[32]  M. Vincent,et al.  Insights into the Activity and Specificity of Trypanosoma cruzi trans-Sialidase from Molecular Dynamics Simulations , 2013, Biochemistry.

[33]  Felicity L. Mitchell,et al.  Tryptophan as a molecular shovel in the glycosyl transfer activity of Trypanosoma cruzi trans-sialidase. , 2010, Biophysical journal.

[34]  Stewart A. Adcock,et al.  Molecular dynamics: survey of methods for simulating the activity of proteins. , 2006, Chemical reviews.

[35]  Christopher W Murray,et al.  Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation. , 2005, Journal of medicinal chemistry.

[36]  A. Doweyko,et al.  Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[37]  E. Springman,et al.  Mutagenesis of p38alpha MAP kinase establishes key roles of Phe169 in function and structural dynamics and reveals a novel DFG-OUT state. , 2010, Biochemistry.

[38]  E. Goldsmith,et al.  The structure of mitogen-activated protein kinase p38 at 2.1-A resolution. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Neil J Bruce,et al.  Ab Initio Protein Folding Using a Cooperative Swarm of Molecular Dynamics Trajectories. , 2010, Journal of chemical theory and computation.

[40]  John Kuriyan,et al.  Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). , 2001, Cancer research.

[41]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

[42]  Harish Vashisth,et al.  "DFG-flip" in the insulin receptor kinase is facilitated by a helical intermediate state of the activation loop. , 2011, Biophysical journal.

[43]  G. Torrie,et al.  Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling , 1977 .

[44]  Fotini Tzortzatou-Stathopoulou,et al.  Conformational dynamics of the EGFR kinase domain reveals structural features involved in activation , 2009, Proteins.

[45]  A. Roitberg,et al.  Modulation of catalytic function by differential plasticity of the active site: case study of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase. , 2009, Biochemistry.

[46]  K. Schulten,et al.  Molecular dynamics study of unbinding of the avidin-biotin complex. , 1997, Biophysical journal.

[47]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[48]  Grubmüller,et al.  Predicting slow structural transitions in macromolecular systems: Conformational flooding. , 1995, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[49]  T. Darden,et al.  A smooth particle mesh Ewald method , 1995 .

[50]  J. Mongan,et al.  Accelerated molecular dynamics: a promising and efficient simulation method for biomolecules. , 2004, The Journal of chemical physics.

[51]  S. Wodak,et al.  Multiple replica repulsion technique for efficient conformational sampling of biological systems. , 2011, Biophysical journal.