The ability of vancomycin-group antibiotics to bind cell-wall fragmentsin vitro proyides a model system for semi-quantitative studies of molecular recognition in aqueous solution. Based upon a partitioning of free energy contributions to binding, we have assessed the surface area-dependent free energy contribution of the hydrophobic effect, the free energy contribution of amide-amide and amide-carboxylate hydrogen bonds, and the cost of restricting σ-bond rotations in the binding of both natural cell-wall analogues and within a family of rationally designed cell-wall mimics. The results so far obtained may provide guiding principles for those interested in semi-quantitative studies of molecular recognition and rational drug design. Vancomycin-group antibiotics have been shown to dimerise, a process now proposed to play a functional role in the mechanism of action. Dimerisation has been shown to be cooperatively enhanced by natural cell-wall peptides. However, studies with ristocetin A show that binding of unnatural structural motifs (particularly those containing aromatic ring systems not found in the natural peptides) and dimerisation, are highly anti-cooperative phenomena.