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Abstract A computational method for exploring the orientational and conformational space of a flexible ligand within a macromolecular receptor site is presented. The approach uses a variant of the DOCK algorithm Kuntz et al., J. Mol. Biol. , 161 , 288 (1982) to determine orientations of a fragment of the ligand within the site. These positions then form the basis for exploring the conformational space of the rest of the ligand, using a systematic search algorithm. The search incorporates a method by which the ligand conformation can be modified in response to interactions with the receptor. The approach is applied to two test cases, in both of which the crystallographically determined structures are obtained. However, alternative models can also be obtained that differ significantly from those observed experimentally. The ability of a variety of measures of the intermolecular interaction to discriminate among these structures is discussed.
Leach et al. (Wed,) studied this question.