Cooperativity, Partially Bound States, and Enthalpy-Entropy Compensation

Abstract

Efforts to develop a quantitative understanding of molecular recognition rely on the additivity of individual intermolecular interactions, and cooperativity represents one of the major potential stumbling blocks. A chemical double-mutant cycle has been used to experimentally measure cooperativity between functional group interactions within a complex framework. The interaction between two aromatic groups varies by 0.2 +/- 0.4 kJ mol(-1) in synthetic H-bonded complexes that differ by 8-13 kJ mol(-1) in overall stability. In these systems, the free energies associated with individual intermolecular interactions can therefore be reliably treated in an additive fashion. The results suggest that alternative explanations should be considered for cooperative phenomena observed in other systems, and a rationale based on the population of partially bound states in flexible molecules is proposed to account for the enthalpic chelate effect and enthalpy-entropy compensation.

Free-energy relationships for the interactions of tryptophan with phosphocholines

“…10 Molecular dynamics simulations of mixed indole-lipid and tryptophan-lipid systems indicate a 50 preference for indole to localise at specific locations in relation to membranes, including the middle of the bilayer, proximal to the choline headgroup and in the region of the lipid carbonyl groups, with the latter being the preferred site. 17,18 This is supported by experimental work on model 55 helical transmembrane peptides bearing interfacial tryptophan residues, for which the presence of hydrogen bonding interactions with lipid carbonyl groups is notable. 19,20 However, an interfacial preference of tryptophan residues is also observed for similar peptides with ether-linked lipids, 21 60 which complements observations on the membrane partitioning behaviour of simple indole derivatives that similarly localise into the headgroup region of these lipids.…”

“…The intramolecular π-facial (NHPy) and hydrogen bonding interactions for tryptophan and cation-carbonyl interactions for DMPC, observed in the single molecule simulations (Fig. 6), were absent from these binding 55 configurations.…”

“…43 Cluster analysis was conducted on a subset of the coordinates comprising the amino acid and lipid headgroup only, using the GROMOS clustering method, 32,44 with rms cut-offs in the range 0.10-0.14 nm, chosen such that the average rms 55 deviation per atom was <0.01 nm. …”

“…Nevertheless, calculated water isotherms could be obtained (Fig. 4B) 55 were negative (in the range -0.2 ppm to -1.1 ppm). As a whole, the complexation-induced shift changes, particularly for Δδ 1 , are in agreement with those observed previously for the interaction of 1c with DAPC.…”

“…in the population of states that involve these intramolecular contacts offsets the reduction in free energy contribution from cation-π interactions. The overall picture, therefore, is of a system of interacting molecules that contains a significant number of partially bound states, with enthalpic co-5 operativity 55 operating to populate specific tightly-bound configurations. a atom numbers correspond to those in Fig.…”