Conformational analysis of flexible ligands in macromolecular receptor sites

A computational method for exploring the orientational and conformational space of a flexible ligand within a macromolecular receptor site is presented. The approach uses a variant of the DOCK algorithm [Kuntz et al., J. Mol. Biol., 161, 288 (1982)] to determine orientations of a fragment of the ligand within the site. These positions then form the basis for exploring the conformational space of the rest of the ligand, using a systematic search algorithm. The search incorporates a method by which the ligand conformation can be modified in response to interactions with the receptor. The approach is applied to two test cases, in both of which the crystallographically determined structures are obtained. However, alternative models can also be obtained that differ significantly from those observed experimentally. The ability of a variety of measures of the intermolecular interaction to discriminate among these structures is discussed.

[1]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[2]  G. Roberts,et al.  Ultraviolet difference-spectroscopic studies of substrate and inhibitor binding to Lactobacillus casei dihydrofolate reductase. , 1978, The Biochemical journal.

[3]  R Langridge,et al.  Real-time color graphics in studies of molecular interactions. , 1981, Science.

[4]  J. Bolin,et al.  Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate. , 1982, The Journal of biological chemistry.

[5]  M. L. Connolly.  Analytical molecular surface calculation , 1983 .

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

[7]  P. Kollman,et al.  An approach to computing electrostatic charges for molecules , 1984 .

[8]  Peter Murray-Rust,et al.  Directional hydrogen bonding to sp2- and sp3-hybridized oxygen atoms and its relevance to ligand-macromolecule interactions , 1984 .

[9]  E. Baker,et al.  Hydrogen bonding in globular proteins. , 1984, Progress in biophysics and molecular biology.

[10]  A. Ghose,et al.  Geometrically feasible binding modes of a flexible ligand molecule at the receptor site , 1985 .

[11]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[12]  I. Kuntz,et al.  Docking flexible ligands to macromolecular receptors by molecular shape. , 1986, Journal of medicinal chemistry.

[13]  C Zimmer,et al.  Nonintercalating DNA-binding ligands: specificity of the interaction and their use as tools in biophysical, biochemical and biological investigations of the genetic material. , 1986, Progress in biophysics and molecular biology.

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

[15]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[16]  Conrad C. Huang,et al.  The MIDAS display system , 1988 .

[17]  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.

[18]  Alexander Rich,et al.  Molecular Structure of the Netropsin-d(CGCGATATCGCG) Complex: DNA Conformation in an Alternating AT Segment , 1989 .

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

[20]  Keith Prout,et al.  The application of Artificial Intelligence to the conformational analysis of strained molecules , 1990 .

[21]  Andrew R. Leach,et al.  Automated conformational analysis: Directed conformational search using the A* algorithm , 1990 .

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

[23]  Binding by design , 1991, Nature.

[24]  Andrew Smellie,et al.  Fast drug-receptor mapping by site-directed distances: a novel method of predicting new pharmacological leads , 1991, J. Chem. Inf. Comput. Sci..