An exploration of a novel strategy for superposing several flexible molecules.

This paper describes a computational strategy for the superposition of a set of flexible molecules. The combinatorial problems of searching conformational space and molecular matching are reduced drastically by the combined use of simulated annealing methods and cluster analysis. For each molecule, the global minimum of the conformational energy is determined by annealing and the search trajectory is retained in a history file. All the significantly different low-energy conformations are extracted by cluster analysis of data in the history file. Each pair of molecules, in each of their significantly different conformations, is then matched by simulated annealing, using the difference-distance matrix as the objective function. A set of match statistics is then obtained, from which the best match taken from all different conformations can be found. The molecules are then superposed either by reference to a base molecule or by a consensus method. This strategy ensures that as wide a range of conformations as possible is considered, but at the same time that the smallest number of significantly different conformations is used. The method has been tested on a set of six angiotensin II antagonists with between 7-11 rotatable bonds.