Towards a More Complete Understanding of Ligand-Receptor Binding: Cooperativity among Ligand Functional Groups, the Role of Water in Binding, and the Thermodynamics of the Hydrophobic Effect
Nasief Abdel-Sayed, Nader N.
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One of the main focuses of the current work was to understand how cooperativity could influence the affinity and the thermodynamics of ligand-receptor binding. For example, one of the studies presented herein investigated whether the relationships among the functional groups/side chains of thermolysin inhibitors are cooperative or additive (chapter 2). This study also correlated the cooperative/additive behavior observed experimentally with certain structural features in the investigated functional groups, such as polarity, distance between the studied groups, and the characteristics of the hydrophobic side chains. Another study presented in this work investigated the thermodynamic (enthalpic and entropic) cooperativity between a Me side chain and a COO- group in thermolysin inhibitors (chapter 3). In this study, thermodynamic cooperativities, which are larger in magnitude than the free energy cooperativity, were observed. These thermodynamic cooperativities were found to be mediated by the changes in the hydration layer of the ligand-protein complex. This role that hydration water molecules could play in the process of ligand-protein binding was previously underappreciated. A third study that provided more insight into the nature of cooperativity and how its magnitude could be variable depending on the details of binding was performed on thrombin inhibitors (chapter 5). Such study revealed that the magnitude of positive cooperativity between H-bonding and hydrophobic interactions is in direct correlation with the number and strength of the H-bonds between the ligand and the protein. A fourth study, which revealed that cooperativity can exist among structural components that are normally unexpected to be influenced by each other (due to the distance among these components and the role they play in binding), is presented in chapter 6. This study demonstrated that there is negative cooperativity between an acyl group at one end of thrombin inhibitors and a meta-chloro substituent at the other end. As this work deals with various complex aspects of binding, and one of these aspects is the hydrophobic effect, one of the studies presented in this work explored the thermodynamics of the hydrophobic effect in the shallow, flat and solvent-exposed hydrophobic S2' pocket of thermolysin (chapter 4). This study investigated the influence of the neighboring COO- group on this thermodynamic signature as well. One of the main conclusions drawn from this study was that the COO- has indeed a strong modulating effect on the thermodynamics of the hydrophobic effect. This effect is mediated by the modulating of the H-bonding/organization status of the hydration waters both in the unbound and the bound states. A remarkable enthalpy-entropy compensation relationship was also observed, reflecting the fact that the hydrophobic effect is governed by the thermodynamic status of the interfacial aqueous environment of the unbound ligand and the ligand-receptor complex. The final study presented herein is a study which investigated the modulation of the H-bond basicity of thrombin inhibitors via bioisosterism (chapter 7). This study revealed that the correlation between the biological activity and the H-bond basicity is not as simple as would be expected at the first glance. This could be because of the involvement of the desolvation factor of the H-bonding groups. One of the factors that impede the development of the field of understanding ligand-receptor binding and predicting the outcomes of structure-activity relationship (SAR) studies is the lack of studies which systematically explore the factors affecting the binding process. (Abstract shortened by UMI.)