Abstract
The W191G cavity of cytochrome c peroxidase is useful as a model system for introducing small molecule oxidation in an artificially created cavity. A set of small, cyclic, organic cations was previously shown to bind in the buried, solvent-filled pocket created by the W191G mutation. We docked these ligands and a set of non-binders in the W191G cavity using AutoDock 3.0. For the ligands, we compared docking predictions with experimentally determined binding energies and X-ray crystal structure complexes. For the ligands, predicted binding energies differed from measured values by ± 0.8 kcal/mol. For most ligands, the docking simulation clearly predicted a single binding mode that matched the crystallographic binding mode within 1.0 Å RMSD. For 2 ligands, where the docking procedure yielded an ambiguous result, solutions matching the crystallographic result could be obtained by including an additional crystallographically observed water molecule in the protein model. For the remaining 2 ligands, docking indicated multiple binding modes, consistent with the original electron density, suggesting disordered binding of these ligands. Visual inspection of the atomic affinity grid maps used in docking calculations revealed two patches of high affinity for hydrogen bond donating groups. Multiple solutions are predicted as these two sites compete for polar hydrogens in the ligand during the docking simulation. Ligands could be distinguished, to some extent, from non-binders using a combination of two trends: predicted binding energy and level of clustering. In summary, AutoDock 3.0 appears to be useful in predicting key structural and energetic features of ligand binding in the W191G cavity.
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Finzel, B.C., Poulos, T.L. and Kraut, J., J. Biol. Chem., 259 (1984) 13027.
Yonetani, T., Enzymes, Academic Press, San Diego, CA, 1976.
Erman, J.E., Vitello, L.B., Miller, M.A., Shaw, A., Brown, K.A. and Kraut, J., Biochemistry, 32 (1993) 9798.
Houseman, A.L., Doan, P.E., Goodin, D.B. and Hoffman, B.M., Biochemistry, 32 (1993) 4430.
Sivaraja, M., Goodin, D.B., Smith, M. and Hoffman, B.M., Science, 245 (1989) 738.
Huyett, J.E., Doan, P.E., Gurgiel, R., Houseman, A.L.P., Sivaraja, M., Goodin, D.B. and Hoffman, B.M., J. Am. Chem. Soc., 117 (1995) 9033.
Musah, R.A. and Goodin, D.B., Biochemistry, 36 (1997) 11665.
Fitzgerald, M.M., Trester, M.L., Jensen, G.M., McRee, D.E. and Goodin, D.B., Protein Sci., 4 (1995) 1844.
Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E., Nucleic Acids Res., 28 (2000) 235.
Fitzgerald, M.M., Churchill, M.J., McRee, D.E. and Goodin, D.B., Biochemistry, 33 (1994) 3807.
Musah, R.A., Jensen, G.M., Bunte, S.W., Rosenfeld, R.J. and Goodin, D.B., J. Mol. Biol., 315 (2002) 845.
Fitzgerald, M.M., Musah, R.A., McRee, D.E. and Goodin, D.B., Nat. Struct. Biol., 3 (1996) 626.
Olson, A.J. and Goodsell, D.S., SAR & QSAR in Environmental Research, 8 (1998) 273.
Minke, W.E., Diller, D.J., Hol, W.G. and Verlinde, C.L., J. Med. Chem., 42 (1999) 1778.
Bernard, P., Kireev, D.B., Chretien, J.R., Fortier, P.L. and Coppet, L., J. Comput.-Aided Mol. Des., 13 (1999) 355.
Gamper, A.M., Winger, R.H., Liedl, K.R., Sotriffer, C.A., Varga, J.M., Kroemer, R.T. and Rode, B.M., J. Med. Chem., 39 (1996) 3882.
Morris, G.M., Goodsell, D.S., Halliday, S., Huey, R., Hart, W.E., Belew, R.K. and Olson, A.J., J. Comput. Chem., 19 (1998) 1639.
Sotriffer, C.A., Flader, W., Winger, R.H., Rode, B.M., Liedl, K.R. and Varga, J.M., Methods, 20 (2000) 280.
Nacro, K., Bienfait, B., Lee, J., Han, K.C., Kang, J.H., Benzaria, S., Lewin, N.E., Bhattacharyya, D.K., Blumberg, P.M. and Marquez, V.E., J. Med. Chem., 43 (2000) 921.
Hyndman, M.E., Verma, S., Rosenfeld, R.J., Anderson, T.J. and Parsons, H.G., Am. J. Physiol. Heart Circulat. Physiol., 282 (2002) H2167.
Rao, M.S. and Olson, A.J., Proteins, 34 (1999) 173.
Laederach, A., Dowd, M.K., Coutinho, P.M. and Reilly, P.J., Proteins, 37 (1999) 166.
Mahmoudian, M., J. Mol. Graph. Model., 15 (1997) 149.
Coutinho, P.M., Dowd, M.K. and Reilly, P.J., Proteins, 27 (1997) 235.
Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Caterina, G., Alagona, G., Profeta Jr, S. and Weiner, P., J. Am. Chem. Soc., 106 (1984) 765.
Bessler, B.H., Merz Jr., K.M. and Kollman, P.A., J. Comput. Chem., 11 (1990) 431.
Weiner, S.J., Kollman, P.A., Nguyen, D.T. and Case, D.A., J. Comput. Chem., 7 (1986) 230.
Stouten, P.F.W., Frömmel, C., Nakamura, H. and Sander, C., Mol. Simul., 10 (1993) 97.
Morris, G.M., Goodsell, D.S., Huey, R. and Olson, A.J., J. Comput.-Aided Mol. Des., 10 (1996) 293.
Jensen, G.M., Goodin, D.B. and Bunte, S.W., J. Phys. Chem., 199 (1996) 954.
Frisch, M.W., GAUSSIAN92/DFT; GAUSSIAN94 Revision B.1, Gaussian, Inc., Pittsburgh, PA, 1995.
Hehre, W.J., Radom, L., Schleyer, P.R. and Pople, J.A., Ab Initio Molecular Orbital Theory, Wiley, New York, 1986.
Goodsell, D.S., Morris, G.M. and Olson, A.J., J. Mol. Recognit., 9 (1996) 1.
Upson, C., Faulhaber, T., Kamins, D., Laidlaw, D., Schlegel, D., Vroom, J., Gurwitz, R. and van Dam, A., IEEE Comp. Graphics App., 9 (1989) 30.
Shoichet, B.K., Leach, A.R. and Kuntz, I.D., Proteins, 34 (1999) 4.
Rarey, M., Kramer, B. and Lengauer, T., Proteins Struct. Funct. Genet., 34 (1999) 17.
Ogata, K. and Wodak, S.J., Protein Eng., 15 (2002) 697.
Ladbury, J.E., Chem. Biol., 3 (1996) 973.
Tilton, R.F., Jr., Singh, U.C., Weiner, S.J., Connolly, M.L., Kuntz, I.D., Jr., Kollman, P.A., Max, N. and Case, D.A., J. Mol. Biol., 192 (1986) 443.
Raymer, M.L., Sanschagrin, P.C., Punch,W.F., Venkataraman, S., Goodman, E.D. and Kuhn, L.A., J. Mol. Biol., 265 (1997) 445.
Osterberg, F., Morris, G.M., Sanner, M.F., Olson, A.J. and Goodsell, D.S., Proteins, 46 (2002) 34.
Rosenfeld, R.J., Garcin, E.D., Panda, K., Andersson, G., Aberg, A., Wallace, A.V., Morris, G.M., Olson, A.J., Stuehr, D.J., Tainer, J.A. and Getzoff, E.D., Biochemistry, 41 (2002) 13915.
Musah, R.A., Jensen, G.M., Rosenfeld, R.J., McRee, D.M., Bunte, S.W. and Goodin, D.B., J. Am. Chem. Soc., 119 (1997) 9083.
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Rosenfeld, R.J., Goodsell, D.S., Musah, R.A. et al. Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling. J Comput Aided Mol Des 17, 525–536 (2003). https://doi.org/10.1023/B:JCAM.0000004604.87558.02
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DOI: https://doi.org/10.1023/B:JCAM.0000004604.87558.02