Molecular recognition by secondary metabolites

Abstract

Aspects of molecular recognition based on the interaction between the vancomycin group of antibiotics and bacterial cell wall precursor analogues are discussed. The energetically unfavourable folding-in of the residue 1 sidechain in vancomycin and ristocetin A is discussed in terms of the favourable entropy associated with simultaneous release of solvent molecules. The effect of the sugar amino substituent on the strength of an adjacent hydrophobic interaction in the vancomycin/acetyl- d-Ala- d-Ala complex is rationalised as an intramolecular “salting-out” of hydrocarbon entities. The slow on-rate for dimerisation of the ristocetin A/ N ifN-diacetyl- l-Lys- d-Ala- d-Ala complex is attributed to the need for the relatively rigid peptide backbone of the antibiotic to be extensively desolvated before dimerisation can occur. Some of these concepts are then applied to understanding the interactions between antibiotics and the minor groove of double-helical DNA, the receptor site with which they have probably evolved to interact. Two structural motifs (π-polarised aromatic rings and deoxy sugars) are postulated to be important in this recognition process. The possible roles of these structural features are discussed.