Systematic search in conformational analysis

• Published in: Journal of molecular structure. Theochem 1996-10, Vol.370 (2), p.157-171
• Main Authors: Beusen, Denise D., Berkley Shands, E.F., Karasek, S.F., Marshall, Garland R., Dammkoehler, Richard A.
• Format: Article
• Language: English
• Subjects: Conformational search; Molecules from aggregate; Sampling method
• ISSN: 0166-1280; 1872-7999
• DOI: 10.1016/S0166-1280(96)04565-4

The coupling of conformation to activity and reactivity is a widely accepted concept, and as such has driven the development of tools which execute conformational searches in rapid and robust fashion [T.F. Havel, Prog. Biophys. Molec. Biol., 56 (1991) 43–78; A.R. Leach, In Rev. Comput. Chem.; K.B. Lipkowitz and D.B. Boyd, Ed.; VCH Publishers, Inc.: New York, N.Y., 1991, Vol. II, pp. 1–55]. Among the aims of these methods are the determination of a complete set of local minima from which the global energy minimum can be identified, or the generation of conformations consistent with constraints derived from SAR or structural studies. Most methods fall into two broad categories: those which are random or stochastic, and those which are systematic. Yet another group consists of those which are based on heuristics and artificial intelligence [A.R. Leach, K. Prout, D.P. Dolata, J. Comput. Chem. 11 (1990) 680–693]. The first category is typified by molecular dynamics [W.F. van Gunsteren and H.J.C. Berendsen, Angew. Chem. Int. Ed. Eng., 29 (1990) 992–1023], Monte Carlo [M.P. Alien and D.J. Tildesley, Computer Simulation of Liquids, Oxford Science Publications, 1989], distance geometry [J.M. Blaney and J.S. Dixon, in K.B. Lipkowitz and D.B. Boyd (Eds.), Reviews in Computational Chemistry, VCH, New York, Vol. 5, pp. 299–335, 1994], and other approaches [M. Saunders, J. Comput. Chem., 10 (1989) 203–208] in which the path by which conformational space is examined is ideally completely random, but bounded by the geometries of covalent bond lengths and angles. In traditional systematic searches, the variable to be examined, e.g. torsion angles, is divided into a regular grid. Each and every grid point is evaluated in a systematic fashion to determine its validity. The path through the grid points is regular and defined. In principle, systematic search can, within the resolution of the grid, identify all sterically allowed conformations of a molecule. Consequently, systematic search is an ideal tool for conformational analysis because it is not path dependent and cannot become entrapped in local minima. In this article we review some of the basics of systematic search, algorithmic improvements that have enhanced its speed, and new developments that have increased its accuracy by moving away from the limitations of a fixed torsional grid.