Summary
Four isomeric forms of the Asn-102 PPE (D 102 N mutant according to the emerging protocol, [Knowles, Science, 236 (1987) 1252–1258]) have been investigated using energy minimization (EM) and molecular dynamics (MD) techniques. MD simulation data for 175 ps are reported for each form (in total 700 ps for about 2500 atoms). The His-57 Nε-protonated forms are calculated to be more stable than the Nδ-protonated ones. The active site region of the most stable form is very similar to that found in the D102N rat trypsin enzyme [Craik et al., Science, 237 (1987) 909–913]. Conformations of the active sites and their hydrogen bond patterns are presented for each of these forms and are compared with the structure of the native enzyme active site. The pH dependent activity of the D102N derivative is discussed.
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References
Allen, L.C., in Weinstein, H. and Green, J.P. (Eds.) Quantum Chemistry in Biomedical Sciences, Annals of the New York Academy of Sciences, Vol. 367, New York, 1981.
Shibata, M., Kieber-Emmons, T., Dutta, S. and Rein, R., Int. J. Quantum Chem. QBS 8 (1981) 409–417.
Bizzozero, S.A. and Dutler, H., Bioorg. Chem. 10 (1981) 46–62.
Warshel, A. and Russell, S., J. Am. Chem. Soc., 108 (1986) 6569–6579.
Craik, C.S., Roczniak, S., Largman, C. and Rutter, J., Science, 237 (1987) 909–913.
Knowles, J.R., Science, 236 (1987) 1252–1258.
Sprang, S., Standing, T., Fletterick, R.J., Stroud, R.M., Finer-Moore, J., Xuong, N.-H., Hamlin, R., Rutter, W.J. and Craik, C.S., Science, 237 (1987) 905–908.
Meyer Jr., E.F. and Presta, L., In Burgen, A.S.V., Roberts, G.C.K. and Tute, M.S. (Eds.) Molecular Graphics and Drug Design, Elsevier Science Publishers, Amsterdam, 1986, pp 307–321.
Meyer, Jr., E.F., Presta, L. and Radhakrishnan, R., J. Am. Chem. Soc., 107 (1985) 4091–4093.
Meyer Jr., E.F., Radhakrishnan, R., Cole, G.M., and Presta, L., J. Mol. Biol., 189 (1986) 533–539.
Hughes, D.L., Sieker, L.C., Bieth, J., Dimicoli, J.-L., J. Mol. Biol., 162 (1982) 645–655.
With an eye to pursuing MD perturbation calculations, the original CF3 terminus at the anilide ring was here substituted with-CH(CH3)2.
Protein Data Bank, See Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Schimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535–542.
Singh, U.C., Weiner, P.K., Caldwell, J. and Kollman, P., AMBER: Assisted Model Building with Energy Refinement Package, Version 2, Department of Pharmaceutical Chemistry, University of California, San Francisco, 1985.
Weiner, S.J., Kollman, P.A., Nguen, D.T. and Case, D.A., J. Comput. Chem., 7 (1986) 230–252.
Singh, U.C. and Kollman, P.A., J. Comput. Chem. 5 (1984) 129–145.
Carlson, G., Molecular Dynamics Studies of Porcine Pancreatic Elastase: The Native State and Complexed to Two Trifluoroacetyl Dipeptide Anilide Inhibitors, Ph. D. Dissertation, Texas A & M University, 1987.
Ryckaert, J.P., Ciccotti, G. and Berendsen, H.J.C., J. Comput. Phys., 23 (1977) 327–341.
Elber, R. and Karplus, M., Science, 235 (1987) 318–321.
Privalov, P.L., FEBS Lett. Suppl., 40 (1974) 140–153.
Suurkuusk, J., Acta Chem. Scand., B28 (1974) 409–417.
Callen, H.B., Thermodynamics, John Wiley and Sons, New York, 1960.
Bachovchin, W.W., Biochemistry, 25 (1986) 7751–7759
Lybrand, T.P., McCammon, J.A. and Wipff, G., Proc. Nat. Acad. Sci. U.S.A., 83 (1986) 833–835.
Bash, P.A., Singh, U.C., Langridge, R. and Kollman, P.A., Science, 236 (1987) 564–568.
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Lesyng, B., Meyer, E.F. Energy minimization and molecular dynamics studies of Asn-102 elastase. J Computer-Aided Mol Des 1, 211–217 (1987). https://doi.org/10.1007/BF01677045
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DOI: https://doi.org/10.1007/BF01677045