A new method for predicting the alignment of flexible molecules and orienting them in a receptor cleft of known structure.

It is not always easy to align flexible compounds with each other or with their binding cleft on a biological macromolecule, and the alignment of nine partly flexible molecules has now been studied. These compounds are heme analogues having either two or three flexible propionate side chains attached to a porphyrin core, and one compound is a close analogue of natural heme. The noncovalent interactions of each compound were predicted using a new version of the program Grid which can take account of the flexibility of the propionate side chains. The Grid results were then analyzed by hierarchical principal component analysis, and this allowed the molecules to be oriented with respect to each other. It also allowed each analogue to be correctly aligned with the receptor cleft for heme in myoglobin, because the alignment of natural heme in that cleft is already known. Factors influencing the predicted alignment are also considered.