An electrostatic surface field point approach to the characterisation of biomolecular interactions

Most of the important properties of molecules are determined by the way they interact with other molecules, and this is particularly true of biomolecules that almost all rely on selective intermolecular interactions for their function. Despite advances in our understanding of intermolecular interactions at the level of simple functional group contacts, such as H-bonding, hydrophobic interaction, aromatic stacking etc, it is still an extremely challenging task to predict the structure of intermolecular complexes of even relatively simple small molecule complexes, let alone protein-protein interactions. The development of fast and accurate methods for computationally estimating the three-dimensional structures and thermodynamic stability of intermolecular complexes remains a major scientific challenge. The state-of-the-art is either all atom simulations, where the force-fields are still too unstable to allow accurate estimation of free energies and the calculations are too large to use in any kind of screening programme, or docking algorithms that use simple empirical scoring functions, which are fast but crude. The research programme proposed here aims somewhere in the middle. We will use methods that have a sound theoretical basis and are sufficiently robust to calculate accurate free energies, combined with a stripped down representation of molecular structure to allow rapid calculations on macromolecules and large compounds libraries. The ability to dock two molecules to predict the structure and stability of the intermolecular complex has obvious applications in all areas of biology and medicine, where protein-ligand, protein-protein, protein-DNA complexes regulate almost all biochemistry in the cell. This is a challenging target and there are many aspects to the problem for which no current solutions exist, eg handling of large scale loop movements in proteins that alter the nature of interaction interfaces, but we will start with simpler systems and gradually work towards these more difficult problems. The academic applicant has developed a computational approach for small molecules that accurately estimates the stability of intermolecular complexes in solution based on a reduced representation of the electrostatic fields of binding partners. The industry partner has developed a computational approach for small molecules that accurately describes the structural properties of intermolecular complexes based on a different representation of the electrostatic field. The aim of this project is to develop a new composite computational method that takes key elements of these two approaches and combines them for the accurate prediction of the structure and stability of biomolecular complexes in solution. This will establish a new tool that could be applied to a wide range of problems in biology. Discovering what small molecules or macromolecules are likely to bind to a specific target protein would be of immense value in progressing from the information contained in genomes to an understanding of the functional biochemistry of living organisms. The approach outlined here provides a promising strategy for improving our chances of success in this endeavour.