Explaining allosteric modulation of protein function by energy/entropy localisation

This project is aligned with BBSRC's strategic research priority -Basic Biosciences underpinning health-, and the strategic plan -exploiting new ways of working-. The aim of the project is to develop a new computational method to characterize the energetic coupling between ligand binding and perturbations in protein dynamics, in the context of the structure-based drug design of allosteric modulators of protein-protein interactions (PPIs).

There is much evidence that innovative treatments for many diseases could be developed by modulating interactions between pairs of proteins with new therapeutic agents. However in many instances, competitive inhibition of a PPI is not tractable with a small-molecule, or the interaction sites may not be accessible to a therapeutic antibody. In those cases, there is much interest in using allosteric mechanisms to modulate the strength of a PPI with small molecules. A strategic objective at UCB is to achieve rational allosteric modulation of PPIs with small molecules. This goal benefits from significant commitments UCB has made to its antibody technology program which greatly facilitate discovery and structural characterization of antibodies as PPI modulators. A recurring need and challenge in this case is to identify they key observed antibody-antigen interactions to recapitulate into a small-molecule scaffold. This requires a very detailed understanding of the key energetic contributions and balance of enthalpic/entropic contributions to binding affinities.

A current strategy to achieve such understanding relies on the combination of biophysical measurements with large-scale molecular dynamics simulations (MD) to reveal functional ligand-induced changes in protein conformations and dynamics. UCB has identified an unmet need in this approach: the availability of MD trajectory analysis tools to characterize energetic coupling between ligand binding and local changes in protein dynamics.

The Michel group at the University of Edinburgh has recently developed a new method to compute solvent entropy at protein interfaces. Two publications have appeared and forthcoming publications described application of the methodology to drug-design problems. The approach has a number of technical advantages over traditional methods, including efficiency and ease of use. The goal of this collaboration is to extend the theoretical and software engineering work done by the Michel group to enable computation of protein entropy with a similar methodology. This will enable UCB to explain: 1) how changes in protein conformation or dynamics influence the binding entropy, enthalpy and free energy of ligands; 2) why some ligands binding to a protein interface cause functional long-range perturbations in protein dynamics, whereas others do not. An answer to these questions would provide the vital clues needed to facilitate the design of allosteric ligands.

This collaboration between academia and industry will make best use of the skills of each partner. The Michel group has expertise in molecular modelling methods development and scientific software engineering. UCB has a general know-how in real world drug discovery and in particular extensive expertise in PPI-ligand interactions. UCB is well placed to effectively integrate this new computational methodology into its robust biophysical technology pipeline for industrial drug discovery. Academia benefits from translation of basic research into a tool useful for industrial drug discovery.

Overall the project will provide an excellent student with a superb opportunity to receive world-class training in the area of protein-ligand interactions, making best use of the outstanding facilities and expertise available at the University of Edinburgh and at UCB.