Improving the Efficiency
of Protein–Ligand
Binding Free-Energy Calculations by System Truncation
GenhedenSamuel
RydeUlf
2016
We have studied whether the efficiency of alchemical
free-energy
calculations with the Bennett acceptance ratio method of protein–ligand
binding energies can be improved by simulating only part of the protein.
To this end, we solvated the full protein in a spherical droplet with
a radius of 46 Å, surrounded by a vacuum. Then, we systematically
reduced the size of the droplet and at the same time ignored protein
residues that were outside the droplet. Radii of 40–15 Å
were tested. Ten inhibitors of the blood clotting factor Xa were studied,
and the results were compared to an earlier study in which the protein
was solvated in a periodic box, showing complete agreement between
the two sets of calculations within statistical uncertainty. We then
show that the simulated system can be truncated down to 15 Å,
without changing the calculated affinities by more than 0.5 kJ/mol
on average (maximum difference of 1.4 kJ/mol). Moreover, we show that
reducing the number of intermediate states in the calculations from
eleven to three gave deviations that, on average, were only 0.5 kJ/mol
(maximum of 1.4 kJ/mol). Together, these results show that truncation
is an appropriate way to improve the efficiency of free-energy calculations
for small mutations that preserve the net charge of the ligand. In
fact, each calculation of a relative binding affinity requires only
six simulations, each of which takes ∼15 CPU h of computation
on a single processor.