Binding free energy methods allow computational chemists to predict whether or not changes to a ligand increase or decrease its binding affinity to a medicinally important protein. While these methods can reveal whether or not a change to the ligand increases its binding affinity, they provide little information as to how this change affects individual molecular interactions. Such information would be extremely useful, as it could provide feedback to a drug designer that could inspire the next series of ligand modifications. For example, it would be valuable for the free energy calculation to reveal that addition of a hydroxyl group to a ligand strengthens its interaction with an active site aspartate residue, but simultaneously destabilises a water molecule that bridges between it and the protein. This feedback could inspire a drug designer to investigate ligand modifications that combine addition of the hydroxyl group with the addition of moeities that displace the bridging water molecule.<br/><br/>We have developed a range of binding free energy methods, based on WaterSwap. These swap-based methods allow calculation of absolute and relative protein-ligand binding free energies using a single simulation over a single λ-coordinate. Use of a single coordinate allows components of the binding free energy (i.e. specific interactions between the ligand and individual active-site residues, or between the ligand and neighbouring water molecules) to be integrated across λ during the simulation. The resulting components are used to colour-code 3D views of the protein-ligand system. This allows drug designers to easily visualise the affect of ligand modifications on the interactions between the ligand and individual residues in the protein, and individual water molecules in the binding site. These components are not true free energies. However, what they reveal is chemically intuitive, and provide a level of insight that allows drug designers to suggest modifications that lead to improved binding affinity. The components show co-operative affects, and also reveal how increasing the strength of interaction between a ligand and active site residues can disrupt and destablise the solvating water network in the binding site.

Understanding protein-ligand binding at the molecular level: Using swap-based methods to visualise binding free energy components

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.