Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes

AbstractThe calculation of hydrogen positions is a common preprocessing step when working with crystal structures of protein-ligand complexes. An explicit description of hydrogen atoms is generally needed in order to analyze the binding mode of particular ligands or to calculate the associated binding energies. Due to the large number of degrees of freedom resulting from different chemical moieties and the high degree of mutual dependence this problem is anything but trivial. In addition to an efficient algorithm to take care of the complexity resulting from complicated hydrogen bonding networks, a robust chemical model is needed to describe effects such as tautomerism and ionization consistently. We present a novel method for the placement of hydrogen coordinates in protein-ligand complexes which takes tautomers and protonation states of both protein and ligand into account. Our method generates the most probable hydrogen positions on the basis of an optimal hydrogen bonding network using an empirical scoring function. The high quality of our results could be verified by comparison to the manually adjusted Astex diverse set and a remarkably low rate of undesirable hydrogen contacts compared to other tools.

[1]  Matthias Rarey,et al.  NAOMI: On the Almost Trivial Task of Reading Molecules from Different File formats , 2011, J. Chem. Inf. Model..

[2]  Riccardo Baron,et al.  Computational Drug Discovery and Design , 2012, Methods in Molecular Biology.

[3]  Glen Eugene Kellogg,et al.  Web application for studying the free energy of binding and protonation states of protein–ligand complexes based on HINT , 2009, J. Comput. Aided Mol. Des..

[4]  M Karplus,et al.  Polar hydrogen positions in proteins: Empirical energy placement and neutron diffraction comparison , 1988, Proteins.

[5]  P. L. Kirk,et al.  THE APPARENT DISSOCIATION CONSTANTS OF ARGININE AND OF LYSINE AND THE APPARENT HEATS OF IONIZATION OF CERTAIN AMINO ACIDS , 1930 .

[6]  Matthias Rarey,et al.  The Valence State Combination Model: A Generic Framework for Handling Tautomers and Protonation States , 2014, J. Chem. Inf. Model..

[7]  Peter Cornelius,et al.  Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR beta subtype-selective thyromimetics. , 2003, Bioorganic & medicinal chemistry letters.

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

[9]  Xin Li,et al.  Assignment of polar states for protein amino acid residues using an interaction cluster decomposition algorithm and its application to high resolution protein structure modeling , 2006, Proteins.

[10]  Andrew Potter,et al.  Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity. , 2005, Journal of medicinal chemistry.

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

[12]  Paul Seiler,et al.  A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F...C=O interactions. , 2003, Angewandte Chemie.

[13]  Roland L. Dunbrack,et al.  Assignment of protonation states in proteins and ligands: combining pKa prediction with hydrogen bonding network optimization. , 2012, Methods in molecular biology.

[14]  Pauline K. Chang,et al.  Synthesis of Some 5-Alkyl-6-azauracils1 , 1958 .

[15]  J. Richardson,et al.  Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. , 1999, Journal of molecular biology.

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

[17]  David Weininger,et al.  SMILES. 2. Algorithm for generation of unique SMILES notation , 1989, J. Chem. Inf. Comput. Sci..

[18]  Matthias Rarey,et al.  Fast automated placement of polar hydrogen atoms in protein-ligand complexes , 2009, J. Cheminformatics.

[19]  C. Sander,et al.  Positioning hydrogen atoms by optimizing hydrogen‐bond networks in protein structures , 1996, Proteins.

[20]  Honggao Yan,et al.  Dynamic roles of arginine residues 82 and 92 of Escherichia coli 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: crystallographic studies. , 2003, Biochemistry.

[21]  David Weininger,et al.  SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules , 1988, J. Chem. Inf. Comput. Sci..

[22]  Didier Rognan,et al.  sc-PDB: an Annotated Database of Druggable Binding Sites from the Protein Data Bank , 2006, J. Chem. Inf. Model..

[23]  Barry Honig,et al.  An assessment of the accuracy of methods for predicting hydrogen positions in protein structures , 2005, Proteins.

[24]  R. Gillespie,et al.  Models of molecular geometry. , 2005, Chemical Society reviews.

[25]  Robert L. Dow.  Discovery of a Novel Series of 6-Azauracil-Based Thyroid Hormone Receptor Ligands: Potent, TRβ Subtype-Selective Thyromimetics. , 2003 .

[26]  P. Labute.  proteins STRUCTURE O FUNCTION O BIOINFORMATICS Protonate3D: Assignment of ionization , 2013 .

[27]  Gert Vriend,et al.  Increasing the precision of comparative models with YASARA NOVA—a self‐parameterizing force field , 2002, Proteins.

[28]  Takayoshi Kinoshita,et al.  Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors. , 2004, Journal of medicinal chemistry.

[29]  Matthias Rarey,et al.  Reading PDB: Perception of Molecules from 3D Atomic Coordinates , 2013, J. Chem. Inf. Model..

[30]  Zukang Feng,et al.  Ligand Depot: a data warehouse for ligands bound to macromolecules , 2004, Bioinform..

[31]  R. Ornstein,et al.  A method for determining the positions of polar hydrogens added to a protein structure that maximizes protein hydrogen bonding , 1992, Proteins.

[32]  K. Wilson,et al.  Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase* , 2004, Journal of Biological Chemistry.

[33]  Adrian A Canutescu,et al.  Access the most recent version at doi: 10.1110/ps.03154503 References , 2003 .