posted on 2013-02-12, 00:00authored byAnita de Ruiter, Chris Oostenbrink
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.