Molecular complexes at a glance: automated generation of two-dimensional complex diagrams

MOTIVATION In this paper a new algorithmic approach is presented, which automatically generates structure diagrams of molecular complexes. A complex diagram contains the ligand, the amino acids of the protein interacting with the ligand and the hydrophilic interactions schematized as dashed lines between the corresponding atoms. The algorithm is based on a combinatorial optimization strategy which solves parts of the layout problem non-heuristically. The depicted molecules are represented as structure diagrams according to the chemical nomenclature. Due to the frequent usage of complex diagrams in the scientific literature as well as in text books dealing with structural biology, biochemistry and medicinal chemistry, the new algorithm is a key element for computer applications in these areas. RESULTS The method was implemented in the new software tool PoseView. It was tested on a representative dataset containing 305 protein-ligand complexes in total from the Brookhaven Protein Data Bank. PoseView was able to find collision-free layouts for more than three quarters of all complexes. In the following the layout generation algorithm is presented and, additional to the statistical results, representative test cases demonstrating the challenges of the layout generation will be discussed. AVAILABILITY The method is available as a webservice at http://www.zbh.uni-hamburg.de/poseview.

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

[2]  J. Wendoloski,et al.  Structural origins of high-affinity biotin binding to streptavidin. , 1989, Science.

[3]  C. Stout,et al.  Crystal structures of aconitase with trans-aconitate and nitrocitrate bound. , 1993, Journal of molecular biology.

[4]  Hans-Joachim Böhm,et al.  The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure , 1994, J. Comput. Aided Mol. Des..

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

[6]  Thomas Lengauer,et al.  Time-Efficient Docking of Flexible Ligands into Active Sites of Proteins , 1995, ISMB.

[7]  F. S. Mathews,et al.  Determination of the gene sequence and the three-dimensional structure at 2.4 angstroms resolution of methanol dehydrogenase from Methylophilus W3A1. , 1996, Journal of molecular biology.

[8]  T L Blundell,et al.  Direct observation by X‐ray analysis of the tetrahedral “intermediate” of aspartic proteinases , 1992, Protein science : a publication of the Protein Society.

[9]  Matthias Rarey,et al.  Automated Drawing of Structural Molecular Formulas under Constraints , 2004, J. Chem. Inf. Model..

[10]  W. Lipscomb,et al.  Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 2,6-bisphosphate, AMP, and Zn2+ at 2.0-A resolution: aspects of synergism between inhibitors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Thomas Lengauer,et al.  A fast flexible docking method using an incremental construction algorithm. , 1996, Journal of molecular biology.

[12]  Harold E. Helson,et al.  Structure Diagram Generation , 2007 .

[13]  G. Schulz,et al.  Substrate specificity and assembly of the catalytic center derived from two structures of ligated uridylate kinase. , 1995, Journal of molecular biology.

[14]  F. A. Quiocho,et al.  Substrate specificity and affinity of a protein modulated by bound water molecules , 1989, Nature.

[15]  J M Thornton,et al.  LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. , 1995, Protein engineering.