Thermodynamics of 'hydrophobic' versus 'hydrophilic' binding in ligand-protein complexes

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Complex biological processes involve the binding of one molecule by another. In some cases this involves the binding of one protein by another, whereas in others the protein binds a small organic molecule ('ligand'). In certain instances, for example in a disease state, there is a need to discover a novel small molecule that binds more tightly (ie has higher affinity) than the natural ligand. Ideally, this novel molecule or 'lead', can be further developed as a drug molecule effective against the particular disease state. The binding process can be thought of as a 'shape' problem, whereby the strength of binding depends critically on shape complementarity between the ligand and the binding pocket on the protein. However, the binding process is more complicated than this, since it is also determined by the extent of dynamics ('floppiness') of the interacting partners. To complicate matters further, there is a third partner in the interaction, namely molecules of solvent water in which all biological interactions take place. The discovery of new drug molecules on the basis of structural information (structure-based drug design) is currently hampered by the lack of information on these additional component parts. For this reason many drugs are discovered by screening large numbers of discrete compounds, which can be very time-consuming. This proposal aims to quantify the contributions to binding affinity from the various components described above. Ultimately, this may enable us to predict binding affinities from protein structures using high-speed computers, thereby inproving the efficiency of the drug discovery process.