58 D. J. Osguthorpe and r! K. C. Paul3.4 ConclusionsMolecular dynamics is an useful implement <strong>in</strong> the ever-grow<strong>in</strong>g arsenal of computationalchemists and <strong>molecular</strong> modellers. It f<strong>in</strong>ds wide application <strong>in</strong> the area ofdrug design. With the advent of more powerful <strong>computer</strong>s it is now possible torout<strong>in</strong>ely <strong>in</strong>clude solvent <strong>in</strong> <strong>molecular</strong> dynamics simulations. This makes feasibledirect comparison with certa<strong>in</strong> experimental conditions. While such simulations areno doubt useful <strong>in</strong> certa<strong>in</strong> conditions, it is useful to keep <strong>in</strong> perspective the overallaim of a <strong>molecular</strong> dynamics study. As shown <strong>in</strong> this article much <strong>in</strong>sight can begathered which <strong>in</strong> turn can be helpful <strong>in</strong> design<strong>in</strong>g more active analogues even by<strong>in</strong> vacuo calculations. This is especially relevant <strong>in</strong> cases where the structure of thereceptor is not known and one has to attempt to <strong>in</strong>fer the b<strong>in</strong>d<strong>in</strong>g site structure fromthe allowed conformations of analogues. In vacuo calculations would br<strong>in</strong>g out mostof the underly<strong>in</strong>g conformations without be<strong>in</strong>g side-tracked by the solvent used <strong>in</strong>the study which <strong>in</strong> turn may not be representative of the b<strong>in</strong>d<strong>in</strong>g environment.References[l] Ramachandran, G. N., Ramakrishnan, C., Sasisekharan, V., J. Mol. Biol. 1963, 7, 95.[2] Ramachandran, G. N., Sasisekharan, V., Adv. Prote<strong>in</strong> Chem. 1968, 23, 283.[3] Scheraga, H. A., Adv. Phys. Org. Chem. 1968, 6, 103.[4] Flory, P. J., <strong>in</strong>: Statistical Mechanics of Cha<strong>in</strong> Molecules, New York-Interscience.J. Wiley and Sons, New York 1969.[5] Liquori, A. M., Q. Rev. Biophys. 1969, 2, 65.[6] Fletcher, R., Powell, M. J. D., Comput. J. 1963, 6, 163.[7] Ermer, O., Struct. Bond. Berl<strong>in</strong> 1976, 27, 161.[8] Fletcher, R., Practical Methods of Optimization 1, Wiley, New York, 1980.[9] McCammon, J. A., Gel<strong>in</strong>, B. R., Karplus, M., Nature 1977, 267, 585.[lo] Crippen, G. M., Havel, T. F., Distance Geometry and Molecular Conformation, JohnWiley and Sons, New York 1988.[ll] McCammon, J. A., Harvey, S. C., Dynamics of Prote<strong>in</strong>s and Nucleic Acids, CambridgeUniversity Press, Cambridge, 1987.[12] Tildesley, D. J., Allen, M. P., Computer Simulations of Liquids, Clarendon Press, Oxford,1987.[13] Dauber-Osguthorpe, P., Roberts, V. A., Osguthorpe, D. J., Wolff, Genest, M., Hagler,A. T., Prote<strong>in</strong> Struct. Funct. Genet. 1988, 4, 31-47.[14] We<strong>in</strong>er, S. J., Kollman, P. A., Case, D. A., S<strong>in</strong>gh, U. C., Ghio, C., Alagona, G., Profeta,S., Jr., We<strong>in</strong>er, P., J. Am. Chem. SOC. 1984, 106, 765-784.[15] Brooks, B. R., Bruccoleri, R. E., Olafson, B. D., States, D. J., Swam<strong>in</strong>athan, S., Karplus,M., J. Comp. Chem. 1983, 4, 187.[16] Wuthrich, K., NMR of Prote<strong>in</strong>s and Nucleic Acids, Wiley-Interscience, 1986.
3 Molecular Dynamics Simulations of Peptides 59[17] Mezei, M., J. Chem. Phys. 1987, 86, 7084-7088.[18] Hagler, A. T., Osguthorpe, D. J., Dauber-Osguthorpe, P., Hempel, J. C., Science 1985,227, 1309-1315.[19] Momany, F. A., J. Am. Chem. Soc. 1976, 98, 2990-3000.[20] Momany, F. A., J. Am. Chem. SOC. 1976, 98, 2996.[21] Struthers, R. S., Rivier, J., Hagler, A. T., Ann. NX Acud. Sci. 1984, 439, 81.[22] Rizo, J., Koerber, S. C., Bienstock, R. J., Rivier, J., Hagler, A. T., Gierasch, L. M.,J. Am. Chem. Soc. 1992, 114, 2852-2859.(231 Dutta, A. S., Gormley, J. J., Mclachlan, P. F. Woodburn, J. R., Biochem. Biophys. Res.Comm. 1989, 159, 1114-1120.[24] Paul, P. K. C., Dauber-Osguthorpe, P., Campbell, M. M., Osguthorpe, D. J., Biochem.Biophys. Res. Comm. 1989, 165, 1051 - 1058.[25] Dutta, A. S., Gormley, J. J., Woodburn, J. R., Paul, P. K. C., Osguthorpe, D. J., Campbell,M. M., Bioorg. Med. Chem. Lett. 1993, 33, 943-948.[26] Gilham, I. D., Baker, B. I., 1 Endocr<strong>in</strong>ol. 1984, 102, 237.[27] Wilkes, B. W., Hruby, V. J., Sherbrooke, W. C., Castrucci, A. M., Hadley, M. E., Science1984, 224, 1111.[28] Baker, B. I., Bird, D. J., Buck<strong>in</strong>gham, J. C., J. Endcr<strong>in</strong>ol. 1985, R5-R8.[29] Skotfitsch, G., Jacobowitz, M., Zamir, N., Bra<strong>in</strong> Res. Bull. 1985, 635.[30] Brown, D. W., Campbell, M. M., K<strong>in</strong>sman, R. G., Moss, C., Paul, P. K. C., Osguthorpe,D. J., Baker, B., J. Chem. SOC. Chem. Commun. 1988, 1543-1545.[31] Paul, P. K. C., Dauber-Osguthorpe, P., Campbell, M. M., Brown, D. W., K<strong>in</strong>sman,R. G., Moss, C., Osguthorpe, D. J., Biopolymers 1990, 29, 623-637.[32] Brown, D. W., Campbell, M. M., K<strong>in</strong>sman, R. G., White, P. D., Moss, C. A.,Osguthorpe, D. J., Paul, P. K. C., Baker, B. I., Biopolymers 1990, 29, 609-622.[33] Cockcroft, V. B., Osguthorpe, D. J., Friday, A. F., Barnard, E. A., Lunt, G. G., Mol.Neurobiol. 1990, 4, 129- 169.[34] Lear, J. D., Wasserman, Z. R., DeGrado, W. F., Science 1988, 240, 1177-1181.[35] BIOSYM Technologies[36] Hol. W. G. J., Halie, L. M., Sander, C., Nature 1981, 294, 532-536.[37] Montal, M. S., Blewitt, R., Tomich, J. M., Montal, M., FEBS Lett. 1992, 313, 12-18.[38] Oiki, S., Madison, V., Montal, M., Prote<strong>in</strong>s 1990, 8, 226-236.[39] Wooley, G. A. Wallace, B. A., J. Membr. Biol. 1992, 129, 109-136.