The development and assessment of computational approaches to the thermodynamics and kinetics of binding

Abstract

Molecular recognition refers to the interaction between two or more molecules through complementary noncovalent bonding, for example, via hydrogen bonding, electrostatic interactions, van der Waals forces or hydrophobic forces. Molecular recognition plays an important role in biology and mediates interactions between receptors and ligands, antigens and antibodies, nucleic acids and proteins, proteins and proteins, enzymes and substrates, and nucleic acids with each other. Many cellular processes are governed by a group of proteins acting in a coordinated manner; such complicated mechanisms are closely regulated: changes in the populations of particular complexes or changes in concentrations of the products of protein mediated reactions can switch cells from one state to another (from replication to apoptosis, for example). These small variations in molecular populations are caused by very delicate differences in the thermodynamics or kinetics of reactions. This implies that in order to understand not only biological systems in terms of their molecular components, but also to be able to predict and model system response to stimuli (whether it is a natural substrate or a drug), characterisation of the thermodynamic and kinetic components of the binding process is of paramount importance. This combined computational-experimental project was focused on the development of new computational approaches able to predict the enthalpic component of ligand binding, using quantum mechanics. A concept of ‘theoceptors’ was developed, which are theoretical receptors constructed by computing the optimal geometry of ligands binding in the receptor. This project was supported by AstraZeneca, and it included an industrial placement in the Structural and Biophysical Sciences area, where the experimental data was generated to characterise the thermodynamics and kinetics of binding of a range of ligands to two biological targets, using two experimental techniques, isothermal titration calorimetry and surface plasmon resonance. The findings contribute greatly to the process currently underway of expanding our understanding of the relevance of both of these aspects of biochemistry to drug discovery.