Using RosettaLigand for Small Molecule Docking into Comparative Models

Computational small molecule docking into comparative models of proteins is widely used to query protein function and in the development of small molecule therapeutics. We benchmark RosettaLigand docking into comparative models for nine proteins built during CASP8 that contain ligands. We supplement the study with 21 additional protein/ligand complexes to cover a wider space of chemotypes. During a full docking run in 21 of the 30 cases, RosettaLigand successfully found a native-like binding mode among the top ten scoring binding modes. From the benchmark cases we find that careful template selection based on ligand occupancy provides the best chance of success while overall sequence identity between template and target do not appear to improve results. We also find that binding energy normalized by atom number is often less than −0.4 in native-like binding modes.

[1]  Jens Meiler,et al.  Design and directed evolution of a dideoxy purine nucleoside phosphorylase. , 2010, Protein engineering, design & selection : PEDS.

[2]  Gerhard Klebe,et al.  Molecular Docking Screens Using Comparative Models of Proteins , 2009, J. Chem. Inf. Model..

[3]  John B. O. Mitchell,et al.  A machine learning approach to predicting protein-ligand binding affinity with applications to molecular docking , 2010, Bioinform..

[4]  Haruki Nakamura,et al.  Announcing the worldwide Protein Data Bank , 2003, Nature Structural Biology.

[5]  Oliver F. Lange,et al.  Structure prediction for CASP8 with all‐atom refinement using Rosetta , 2009, Proteins.

[6]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[7]  Dario Ghersi,et al.  SITEHOUND-web: a server for ligand binding site identification in protein structures , 2009, Nucleic Acids Res..

[8]  Nir London,et al.  Assessing the energy landscape of CAPRI targets by FunHunt , 2007, Proteins.

[9]  Michal Brylinski,et al.  Q‐Dock: Low‐resolution flexible ligand docking with pocket‐specific threading restraints , 2008, J. Comput. Chem..

[10]  Ulrich Rester,et al.  Dock around the Clock – Current Status of Small Molecule Docking and Scoring , 2006 .

[11]  K. Dill,et al.  Assessment of the protein‐structure refinement category in CASP8 , 2009, Proteins.

[12]  Akbar Nayeem,et al.  A comparative study of available software for high‐accuracy homology modeling: From sequence alignments to structural models , 2006, Protein science : a publication of the Protein Society.

[13]  C. E. Peishoff,et al.  A critical assessment of docking programs and scoring functions. , 2006, Journal of medicinal chemistry.

[14]  Ajay N. Jain.  Effects of protein conformation in docking: improved pose prediction through protein pocket adaptation , 2009, J. Comput. Aided Mol. Des..

[15]  David E. Kim,et al.  Physically realistic homology models built with ROSETTA can be more accurate than their templates. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Edgar Jacoby,et al.  Evaluation of the utility of homology models in high throughput docking , 2007, Journal of molecular modeling.

[17]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[18]  Yang Zhang,et al.  I‐TASSER: Fully automated protein structure prediction in CASP8 , 2009, Proteins.

[19]  David Baker,et al.  Blind docking of pharmaceutically relevant compounds using RosettaLigand , 2009, Protein science : a publication of the Protein Society.

[20]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[21]  Jonathan W. Essex,et al.  A review of protein-small molecule docking methods , 2002, J. Comput. Aided Mol. Des..

[22]  Akansha Saxena,et al.  The basic concepts of molecular modeling. , 2009, Methods in enzymology.

[23]  Jens Meiler,et al.  Small Molecule Rotamers Enable Simultaneous Optimization of Small Molecule and Protein Degrees of Freedom in ROSETTALIGAND Docking , 2008 .

[24]  Samuel L. DeLuca,et al.  Practically Useful: What the Rosetta Protein Modeling Suite Can Do for You , 2010, Biochemistry.

[25]  Leo S. D. Caves,et al.  Bio3d: An R Package , 2022 .

[26]  A. Konagurthu,et al.  MUSTANG: A multiple structural alignment algorithm , 2006, Proteins.

[27]  Jens Meiler,et al.  ROSETTALIGAND: Protein–small molecule docking with full side‐chain flexibility , 2006, Proteins.

[28]  J. Mccammon,et al.  Computational drug design accommodating receptor flexibility: the relaxed complex scheme. , 2002, Journal of the American Chemical Society.

[29]  Michal Brylinski,et al.  Q‐DockLHM: Low‐resolution refinement for ligand comparative modeling , 2009, J. Comput. Chem..

[30]  P. Bradley,et al.  Toward High-Resolution de Novo Structure Prediction for Small Proteins , 2005, Science.

[31]  Lars Malmström,et al.  Structure prediction for CASP7 targets using extensive all‐atom refinement with Rosetta@home , 2007, Proteins.

[32]  D. Baker,et al.  Design of a Novel Globular Protein Fold with Atomic-Level Accuracy , 2003, Science.

[33]  Pedro Alexandrino Fernandes,et al.  Protein–ligand docking: Current status and future challenges , 2006, Proteins.

[34]  R. Blakely,et al.  Structural determinants of species‐selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies , 2009, Proteins.

[35]  E. Coutsias,et al.  Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling , 2009, Nature Methods.

[36]  Alexander D. MacKerell,et al.  Computational Fragment-Based Binding Site Identification by Ligand Competitive Saturation , 2009, PLoS Comput. Biol..

[37]  A. Lesk,et al.  The relation between the divergence of sequence and structure in proteins. , 1986, The EMBO journal.

[38]  Richard J. Hall,et al.  Protein-Ligand Docking against Non-Native Protein Conformers , 2008, J. Chem. Inf. Model..

[39]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1978, Archives of biochemistry and biophysics.

[40]  Thomas A. Halgren,et al.  Identifying and Characterizing Binding Sites and Assessing Druggability , 2009, J. Chem. Inf. Model..

[41]  Michael K. Gilson,et al.  Screening Drug-Like Compounds by Docking to Homology Models: A Systematic Study , 2006, J. Chem. Inf. Model..

[42]  Iakes Ezkurdia,et al.  Target domain definition and classification in CASP8 , 2009, Proteins.

[43]  B. Shoichet,et al.  Information decay in molecular docking screens against holo, apo, and modeled conformations of enzymes. , 2003, Journal of medicinal chemistry.

[44]  Jacob D. Durrant,et al.  NNScore 2.0: A Neural-Network Receptor–Ligand Scoring Function , 2011, J. Chem. Inf. Model..

[45]  J M Blaney,et al.  A geometric approach to macromolecule-ligand interactions. , 1982, Journal of molecular biology.