Automated docking of ligands to antibodies: methods and applications.

Many approaches to studying protein-ligand interactions by computational docking are currently available. Given the structures of a protein and a ligand, the ultimate goal of all docking methods is to predict the structure of the resulting complex. This requires a suitable representation of molecular structures and properties, search algorithms to efficiently scan the configuration space for favorable interaction geometries, and accurate scoring functions to evaluate and rank the generated orientations. For many of the available methods, tests on experimentally known antibody-antigen or antibody-hapten complexes have appeared in the literature. In addition, some of them have been used in predictive studies on antibody-ligand interactions to provide structural insights where adequate experimental information is missing. The AutoDock program is presented as example of a method for flexibly docking ligands to antibodies. Applying parameters of the second-generation AMBER force field, three antibody-hapten complexes (AN02, DB3, NC6.8) are used as new test cases to analyze the ability of the method to reproduce experimental findings. The X-ray structures could be reconstituted and the corresponding solutions were ranked with best energy score in all cases. Docking to the free instead of the complexed NC6.8 structure indicated the limits of the rigid protein treatment, although fairly good guesses about the location of the binding site and the contact residues could still be obtained if conformational flexibility was allowed at least in the ligand.

[1]  I. Kuntz,et al.  Characterization of receptors with a new negative image: Use in molecular docking and lead optimization , 1998, Proteins.

[2]  M J Sternberg,et al.  New algorithm to model protein-protein recognition based on surface complementarity. Applications to antibody-antigen docking. , 1992, Journal of molecular biology.

[3]  A. Edmundson,et al.  Local and transmitted conformational changes on complexation of an anti-sweetener Fab. , 1994, Journal of molecular biology.

[4]  J. Janin,et al.  Rigid‐body docking with mutant constraints of influenza hemagglutinin with antibody HC19 , 1994, Proteins.

[5]  I A Vakser.  Long-distance potentials: an approach to the multiple-minima problem in ligand-receptor interaction. , 1996, Protein engineering.

[6]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[7]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[8]  F E Cohen,et al.  Modeling protein-ligand complexes. , 1996, Current opinion in structural biology.

[9]  P. Kollman,et al.  Application of RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvation , 1993 .

[10]  E Rovida,et al.  Modelling antibody-antigen interactions: ferritin as a case study. , 1995, Molecular immunology.

[11]  David E. Clark,et al.  Evolutionary algorithms in computer-aided molecular design , 1996, J. Comput. Aided Mol. Des..

[12]  S Vajda,et al.  Flexible docking and design. , 1995, Annual review of biophysics and biomolecular structure.

[13]  A J Olson,et al.  Automated docking in crystallography: Analysis of the substrates of aconitase , 1993, Proteins.

[14]  I. Wilson,et al.  Structural evidence for induced fit as a mechanism for antibody-antigen recognition. , 1994, Science.

[15]  M J Sternberg,et al.  Predictive docking of protein-protein and protein-DNA complexes. , 1998, Current opinion in structural biology.

[16]  B. Rode,et al.  Ligand binding by antibody IgE Lb4: assessment of binding site preferences using microcalorimetry, docking, and free energy simulations. , 1999, Biophysical journal.

[17]  Elaine C. Meng,et al.  Evaluating docked complexes with the HINT exponential function and empirical atomic hydrophobicities , 1994, J. Comput. Aided Mol. Des..

[18]  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..

[19]  P. Coutinho,et al.  Automated docking of glucosyl disaccharides in the glucoamylase active site , 1997, Proteins.

[20]  S Vajda,et al.  Empirical free energy as a target function in docking and design: application to HIV‐1 protease inhibitors , 1996, FEBS letters.

[21]  J. Tainer,et al.  Predicting molecular interactions and inducible complementarity: Fragment docking of fab‐peptide complexes , 1994, Proteins.

[22]  Johan Desmet,et al.  The dead-end elimination theorem and its use in protein side-chain positioning , 1992, Nature.

[23]  Jurgen Sygusch,et al.  High resolution fast quantitative docking using fourier domain correlation techniques , 1997, Proteins.

[24]  H J Berendsen,et al.  Molecular dynamics simulation of the docking of substrates to proteins , 1994, Proteins.

[25]  J. Stewart,et al.  Rethinking "shape space": evidence from simulated docking suggests that steric shape complementarity is not limiting for antibody-antigen recognition and idiotypic interactions. , 1994, Journal of theoretical biology.

[26]  M. Karplus,et al.  Docking by Monte Carlo minimization with a solvation correction: Application to an FKBP—substrate complex , 1997 .

[27]  Thomas Lengauer,et al.  Computational methods for biomolecular docking. , 1996, Current opinion in structural biology.

[28]  J. Bajorath,et al.  Computational biochemistry of antibodies and T-cell receptors. , 1996, Advances in protein chemistry.

[29]  A. Lesk,et al.  Canonical structures for the hypervariable regions of immunoglobulins. , 1987, Journal of molecular biology.

[30]  M. Karplus,et al.  Functionality maps of binding sites: A multiple copy simultaneous search method , 1991, Proteins.

[31]  C. DeLisi,et al.  Computing the structure of bound peptides. Application to antigen recognition by class I major histocompatibility complex receptors. , 1993, Journal of molecular biology.

[32]  David E. Clark,et al.  A comparison of heuristic search algorithms for molecular docking , 1997, J. Comput. Aided Mol. Des..

[33]  J Moult,et al.  Docking by least-squares fitting of molecular surface patterns. , 1992, Journal of molecular biology.

[34]  C. Lim,et al.  Prediction of an anti-IgE binding site on IgE. , 1998, Protein engineering.

[35]  M. Sternberg,et al.  Modelling protein docking using shape complementarity, electrostatics and biochemical information. , 1997, Journal of molecular biology.

[36]  P Willett,et al.  Docking small-molecule ligands into active sites. , 1995, Current opinion in biotechnology.

[37]  Randy J. Read,et al.  A multiple‐start Monte Carlo docking method , 1992 .

[38]  J. Janin,et al.  Protein‐protein recognition analyzed by docking simulation , 1991, Proteins.

[39]  Christoph A. Sotriffer,et al.  Comparative docking studies on ligand binding to the multispecific antibodies IgE-La2 and IgE-Lb4 , 1996, J. Comput. Aided Mol. Des..

[40]  D E Koshland,et al.  Molecular recognition analyzed by docking simulations: the aspartate receptor and isocitrate dehydrogenase from Escherichia coli. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. S. Dixon,et al.  Evaluation of the CASP2 docking section , 1997, Proteins.

[42]  B. Rode,et al.  Prediction of IgE(Lb4)–ligand complex structures by automated docking , 1996, Journal of molecular recognition : JMR.

[43]  Pieter F. W. Stouten,et al.  A molecular mechanics/grid method for evaluation of ligand–receptor interactions , 1995, J. Comput. Chem..

[44]  Brian K. Shoichet,et al.  Molecular docking using shape descriptors , 1992 .

[45]  J. Cherfils,et al.  Molecular docking programs successfully predict the binding of a β-lactamase inhibitory protein to TEM-1 β-lactamase , 1996, Nature Structural Biology.

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

[47]  J. Janin,et al.  Protein docking algorithms: simulating molecular recognition , 1993 .

[48]  S Vajda,et al.  Prediction of protein complexes using empirical free energy functions , 1996, Protein science : a publication of the Protein Society.

[49]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[50]  A. Leach,et al.  Ligand docking to proteins with discrete side-chain flexibility. , 1994, Journal of molecular biology.

[51]  H A Scheraga,et al.  Reaching the global minimum in docking simulations: a Monte Carlo energy minimization approach using Bezier splines. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  I. Kuntz,et al.  Molecular docking to ensembles of protein structures. , 1997, Journal of molecular biology.

[53]  A. N. Jain,et al.  Hammerhead: fast, fully automated docking of flexible ligands to protein binding sites. , 1996, Chemistry & biology.

[54]  E. Mehler,et al.  Electrostatic effects in proteins: comparison of dielectric and charge models. , 1991, Protein engineering.

[55]  D. Goodsell,et al.  Automated docking of substrates to proteins by simulated annealing , 1990, Proteins.

[56]  Yuan-Ping Pang,et al.  Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies , 1994, J. Comput. Aided Mol. Des..

[57]  Jill E. Gready,et al.  Identification and energetic ranking of possible docking sites for pterin on dihydrofolate reductase , 1998, J. Comput. Aided Mol. Des..

[58]  I. Kuntz,et al.  Structure-Based Molecular Design , 1994 .

[59]  Gerhard Sagerer,et al.  Estimation and filtering of potential protein-protein docking positions , 1998, Bioinform..

[60]  Daniel A. Gschwend,et al.  Orientational sampling and rigid-body minimization in molecular docking revisited: On-the-fly optimization and degeneracy removal , 1996, J. Comput. Aided Mol. Des..

[61]  A Tramontano,et al.  PUZZLE: a new method for automated protein docking based on surface shape complementarity. , 1994, Journal of molecular biology.

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

[63]  R J Read,et al.  Critical evaluation of the research docking program for the CASP2 challenge , 1997, Proteins.

[64]  M. Helmer-Citterich,et al.  Structural studies on an inhibitory antibody against Thermus aquaticus DNA polymerase suggest mode of inhibition. , 1998, Protein Engineering.

[65]  S Doniach,et al.  Computer simulation of antibody binding specificity , 1993, Proteins.

[66]  David S. Goodsell,et al.  Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4 , 1996, J. Comput. Aided Mol. Des..

[67]  A. Edmundson,et al.  Intramolecular signaling upon complexation , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[68]  N. Metropolis,et al.  Equation of State Calculations by Fast Computing Machines , 1953, Resonance.

[69]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[70]  A T Brünger,et al.  2.9 A resolution structure of an anti-dinitrophenyl-spin-label monoclonal antibody Fab fragment with bound hapten. , 1991, Journal of molecular biology.

[71]  R. Glen,et al.  Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. , 1995, Journal of molecular biology.

[72]  H. Wolfson,et al.  Molecular surface complementarity at protein-protein interfaces: the critical role played by surface normals at well placed, sparse, points in docking. , 1995, Journal of molecular biology.

[73]  J. Scott Dixon,et al.  Flexible ligand docking using a genetic algorithm , 1995, J. Comput. Aided Mol. Des..

[74]  I. Kuntz,et al.  Matching chemistry and shape in molecular docking. , 1993, Protein engineering.

[75]  S. Kim,et al.  "Soft docking": matching of molecular surface cubes. , 1991, Journal of molecular biology.

[76]  R. Nussinov,et al.  A geometry-based suite of molecular docking processes. , 1995, Journal of molecular biology.

[77]  G Cesareni,et al.  Escher: A new docking procedure applied to the reconstruction of protein tertiary structure , 1997, Proteins.

[78]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[79]  P. Coutinho,et al.  Automated docking of monosaccharide substrates and analogues and methyl α‐Acarviosinide in the glucoamylase active site , 1997, Proteins.

[80]  J. Gready,et al.  Molecular dynamics simulations of the docking of substituted N5-deazapterins to dihydrofolate reductase. , 1997, Protein engineering.

[81]  R L Stanfield,et al.  Crystal structures of an antibody to a peptide and its complex with peptide antigen at 2.8 A. , 1992, Science.

[82]  I. Haneef,et al.  A robust and efficient automated docking algorithm for molecular recognition. , 1992, Protein engineering.

[83]  B. Rode,et al.  Heteroligation of a mouse monoclonal IgE antibody (La2) with small molecules, analysed by computer-aided automated docking. , 1996, Molecular immunology.

[84]  D S Goodsell,et al.  Automated docking of flexible ligands: Applications of autodock , 1996, Journal of molecular recognition : JMR.

[85]  Ruben Abagyan,et al.  Detailed ab initio prediction of lysozyme–antibody complex with 1.6 Å accuracy , 1994, Nature Structural Biology.

[86]  Haruki Nakamura,et al.  Flexible docking of a ligand peptide to a receptor protein by multicanonical molecular dynamics simulation , 1997 .

[87]  D. Covell,et al.  Docking enzyme‐inhibitor complexes using a preference‐based free‐energy surface , 1996, Proteins.

[88]  M. Mahmoudian,et al.  The cannabinoid receptor: computer-aided molecular modeling and docking of ligand. , 1997, Journal of molecular graphics & modelling.

[89]  P. Kollman,et al.  An all atom force field for simulations of proteins and nucleic acids , 1986, Journal of computational chemistry.

[90]  M. Sternberg,et al.  Rapid refinement of protein interfaces incorporating solvation: application to the docking problem. , 1998, Journal of molecular biology.

[91]  E. Katchalski‐Katzir,et al.  Molecular surface recognition: determination of geometric fit between proteins and their ligands by correlation techniques. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[92]  D. Schomburg,et al.  Hydrogen bonding and molecular surface shape complementarity as a basis for protein docking. , 1996, Journal of molecular biology.

[93]  Andreas Plückthun,et al.  Docking small ligands in flexible binding sites , 1998 .

[94]  T. Lybrand.  Ligand-protein docking and rational drug design. , 1995, Current Opinion in Structural Biology.

[95]  Hans-Joachim Böhm,et al.  Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs , 1998, J. Comput. Aided Mol. Des..

[96]  Ian A. Wilson,et al.  Molecular basis of crossreactivity and the limits of antibody–antigen complementarity , 1993, Nature.

[97]  Harold A. Scheraga,et al.  B‐spline method for energy minimization in grid‐based molecular mechanics calculations , 1998 .

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