Computation of the binding of fully flexible peptides to proteins with flexible side chains

Docking algorithms play an important role in the process of rational drug design and in understanding the mechanism of molecular recognition. An important determinant for successful docking is the extent to which the configurational space (including conformational changes) of the li‐gand/receptor system is searched. Here we describe a new, combinatorial method for flexible docking of peptides to proteins that allows full rotation around all single bonds of the peptide ligand and around those of a large set of receptor side chains. We have simulated the binding of several viral peptides to murine major histocompatibility complex class I H‐2Kb. In addition, we have explored the limits of our method by simulating a complex between calmodulin and an 18‐residue long helical peptide from calmodulin‐dependent protein kinase IIα. The calculated peptide conformations generally matched well with the X‐ray structures. Essential information about local flexibility and about residues that are responsible for strong binding was obtained. We have frequently observed considerable side‐chain flexibility during the simulations, showing the need for a flexible treatment of the receptor. Our method may also be useful whenever the receptor side‐chain conformation is not available or uncertain, as illustrated by the docking of an H‐2Kb binding nonapeptide to the receptor structure taken from an octapeptide/H‐2Kb complex.—Desmet, J., Wilson, I. A., Joniau, M., De Maeyer, M., Lasters, I. Computation of the binding of fully flexible peptides to proteins with flexible side chains. FASEB J 11, 164‐172 (1997)

[1]  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.

[2]  A Caflisch,et al.  Monte Carlo docking of oligopeptides to proteins , 1992, Proteins.

[3]  P. A. Peterson,et al.  Crystal structure of an H-2Kb-ovalbumin peptide complex reveals the interplay of primary and secondary anchor positions in the major histocompatibility complex binding groove. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Robert M. Stroud,et al.  The accuracy of refined protein structures: comparison of two independently refined models of bovine trypsin , 1978 .

[5]  I Lasters,et al.  Enhanced dead-end elimination in the search for the global minimum energy conformation of a collection of protein side chains. , 1995, Protein engineering.

[6]  I. Kuntz,et al.  Using shape complementarity as an initial screen in designing ligands for a receptor binding site of known three-dimensional structure. , 1988, Journal of medicinal chemistry.

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

[8]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[9]  Phillip J. McKerrow,et al.  Introduction to robotics , 1991 .

[10]  John J. Craig,et al.  Introduction to Robotics Mechanics and Control , 1986 .

[11]  Marc De Maeyer,et al.  The “Dead-End Elimination” Theorem: A New Approach to the Side-Chain Packing Problem , 1994 .

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

[13]  R. Goldstein Efficient rotamer elimination applied to protein side-chains and related spin glasses. , 1994, Biophysical journal.

[14]  P. A. Peterson,et al.  Emerging principles for the recognition of peptide antigens by MHC class I molecules. , 1992, Science.

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

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

[17]  S Vajda,et al.  Toward computational determination of peptide‐receptor structure , 1993, Protein science : a publication of the Protein Society.

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

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

[20]  H. Rammensee,et al.  Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules , 1991, Nature.

[21]  W. Howe,et al.  Computer design of bioactive molecules: A method for receptor‐based de novo ligand design , 1991, Proteins.

[22]  F A Quiocho,et al.  Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin-peptide complex. , 1992, Science.

[23]  I. Lasters,et al.  The fuzzy-end elimination theorem: correctly implementing the side chain placement algorithm based on the dead-end elimination theorem. , 1993, Protein engineering.

[24]  J. Janin,et al.  Computer analysis of protein-protein interaction. , 1978, Journal of molecular biology.

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

[26]  Molecular basis of enzyme catalysis and control , 1971, Pure and applied chemistry. Chimie pure et appliquee.

[27]  F A Quiocho,et al.  Modulation of calmodulin plasticity in molecular recognition on the basis of x-ray structures. , 1993, Science.

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

[29]  P. A. Peterson,et al.  Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. , 1994, Science.

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

[31]  T K Sawyer,et al.  HIV protease (HIV PR) inhibitor structure-activity-selectivity, and active site molecular modeling of high affinity Leu [CH(OH)CH2]Val modified viral and nonviral substrate analogs. , 2009, International journal of peptide and protein research.

[32]  S Vajda,et al.  Flexible docking of peptides to class I major-histocompatibility-complex receptors. , 1995, Genetic analysis : biomolecular engineering.

[33]  Roland L. Dunbrack,et al.  Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains , 1994, Nature Structural Biology.

[34]  Ruth Nussinov,et al.  An automated computer vision and robotics-based technique for 3-D flexible biomolecular docking and matching , 1995, Comput. Appl. Biosci..

[35]  P. A. Peterson,et al.  Quantitation of peptide anchor residue contributions to class I major histocompatibility complex molecule binding. , 1993, The Journal of biological chemistry.

[36]  R. Bruccoleri Conformational Search and Protein Folding , 1994 .

[37]  I. Kuntz,et al.  Protein docking and complementarity. , 1991, Journal of molecular biology.

[38]  Shoshana J. Wodak,et al.  Interactive computer animation of macromolecules , 1984 .

[39]  R L Stanfield,et al.  Protein-peptide interactions. , 1995, Current opinion in structural biology.