The good, the bad and the twisted: a survey of ligand geometry in protein crystal structures

The protein databank now contains the structures of over 11,000 ligands bound to proteins. These structures are invaluable in applied areas such as structure-based drug design, but are also the substrate for understanding the energetics of intermolecular interactions with proteins. Despite their obvious importance, the careful analysis of ligands bound to protein structures lags behind the analysis of the protein structures themselves. We present an analysis of the geometry of ligands bound to proteins and highlight the role of small molecule crystal structures in enabling molecular modellers to critically evaluate a ligand model’s quality and investigate protein-induced strain.

[1]  Robin Taylor,et al.  Validating and Understanding Ring Conformations Using Small Molecule Crystallographic Data , 2012, J. Chem. Inf. Model..

[2]  K. Dill,et al.  Binding of small-molecule ligands to proteins: "what you see" is not always "what you get". , 2009, Structure.

[3]  Xuliang Jiang,et al.  Crystal structure of inhibitor of κB kinase β (IKKβ) , 2011, Nature.

[4]  Jonas Boström,et al.  Conformational energy penalties of protein-bound ligands , 1998, J. Comput. Aided Mol. Des..

[5]  Angel R de Lera,et al.  Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10 , 2007, Proceedings of the National Academy of Sciences.

[6]  Xuliang Jiang,et al.  Crystal structure of inhibitor of kappaB kinase beta. , 2011 .

[7]  Sameer Velankar,et al.  Implementing an X-ray validation pipeline for the Protein Data Bank , 2012, Acta crystallographica. Section D, Biological crystallography.

[8]  Gerhard Klebe,et al.  Relibase: design and development of a database for comprehensive analysis of protein-ligand interactions. , 2003, Journal of molecular biology.

[9]  I. Kuntz,et al.  The maximal affinity of ligands. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Martin Stahl,et al.  Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis , 2008, J. Chem. Inf. Model..

[11]  T. A. Jones,et al.  The Uppsala Electron-Density Server. , 2004, Acta crystallographica. Section D, Biological crystallography.

[12]  Keith T. Butler,et al.  Toward accurate relative energy predictions of the bioactive conformation of drugs , 2009, J. Comput. Chem..

[13]  Jie Luo,et al.  Retrieval of Crystallographically-Derived Molecular Geometry Information , 2004, J. Chem. Inf. Model..

[14]  Paul N. Mortenson,et al.  Diverse, high-quality test set for the validation of protein-ligand docking performance. , 2007, Journal of medicinal chemistry.

[15]  Robin Taylor,et al.  Comparison of conformer distributions in the crystalline state with conformational energies calculated by ab initio techniques , 1996, J. Comput. Aided Mol. Des..

[16]  Julian Tirado-Rives,et al.  Contribution of conformer focusing to the uncertainty in predicting free energies for protein-ligand binding. , 2006, Journal of medicinal chemistry.

[17]  C L Brooks,et al.  Do active site conformations of small ligands correspond to low free-energy solution structures? , 1998, Journal of computer-aided molecular design.

[18]  Gerard J Kleywegt,et al.  Limitations and lessons in the use of X-ray structural information in drug design , 2008, Drug Discovery Today.

[19]  C. Macrae,et al.  Mercury CSD 2.0 – new features for the visualization and investigation of crystal structures , 2008 .

[20]  Claudio Luchinat,et al.  Entropic contribution to the linking coefficient in fragment based drug design: a case study. , 2010, Journal of medicinal chemistry.

[21]  D. Metzler,et al.  Refinement and Comparisons of the Crystal Structures of Pig Cytosolic Aspartate Aminotransferase and Its Complex with 2-Methylaspartate* , 1997, The Journal of Biological Chemistry.

[22]  L. Mario Amzel,et al.  Impact of linker strain and flexibility in the design of a fragment-based inhibitor , 2009, Nature chemical biology.

[23]  Robin Taylor,et al.  A new test set for validating predictions of protein–ligand interaction , 2002, Proteins.

[24]  Irene T Weber,et al.  Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114. , 2006, Journal of molecular biology.

[25]  Omar Haq,et al.  Torsion Angle Preference and Energetics of Small-Molecule Ligands Bound to Proteins , 2007, J. Chem. Inf. Model..

[26]  Xue Li,et al.  Accurate assessment of the strain energy in a protein‐bound drug using QM/MM X‐ray refinement and converged quantum chemistry , 2011, J. Comput. Chem..

[27]  Gerard J. Kleywegt,et al.  On vital aid: the why, what and how of validation , 2009, Acta crystallographica. Section D, Biological crystallography.

[28]  Ajay N. Jain,et al.  Molecular Shape and Medicinal Chemistry: A Perspective , 2010, Journal of medicinal chemistry.

[29]  Gerard J. Kleywegt,et al.  Crystallographic refinement of ligand complexes , 2006, Acta crystallographica. Section D, Biological crystallography.

[30]  P. Charifson,et al.  Conformational analysis of drug-like molecules bound to proteins: an extensive study of ligand reorganization upon binding. , 2004, Journal of medicinal chemistry.

[31]  Gallego Oriol,et al.  腫ようマーカーAKR1B10の高いall‐trans‐レチンアルデヒドレダクターゼ活性に対する構造的基礎 , 2007 .

[32]  F. Allen.  The Cambridge Structural Database: a quarter of a million crystal structures and rising. , 2002, Acta crystallographica. Section B, Structural science.

[33]  Gerard J Kleywegt,et al.  Application and limitations of X-ray crystallographic data in structure-based ligand and drug design. , 2003, Angewandte Chemie.

[34]  Vincent Breton,et al.  PDB_REDO: automated re-refinement of X-ray structure models in the PDB , 2009, Journal of applied crystallography.