Protein–Ligand Binding from Distancefield Distances and Hamiltonian Replica Exchange Simulations

The calculation of protein–ligand binding free energies is an important goal in the field of computational chemistry. Applying path-sampling methods for this purpose involves calculating the associated potential of mean force (PMF) and gives insight into the binding free energy along the binding process. Without a priori knowledge about the binding path, sampling reversible binding can be difficult to achieve. To alleviate this problem, we introduce the distancefield (DF) as a reaction coordinate for such calculations. DF is a grid-based method in which the shortest distance between the binding site and a ligand is determined avoiding routes that pass through the protein. Combining this reaction coordinate with Hamiltonian replica exchange molecular dynamics (HREMD) allows for the reversible binding of the ligand to the protein. A comparison is made between umbrella sampling using regular distance restraints and HREMD with DF restraints to study aspirin binding to the protein phospholipase A₂. Although the free energies of binding are similar for both methods, the increased sampling with HREMD has a significant influence on the shape of the PMF. A remarkable agreement between the calculated binding free energies from the PMF and the experimental estimate is obtained.