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Can System Truncation Speed up Ligand-Binding Calculations with Periodic Free-Energy Simulations?

Journal article
Authors Francesco Manzoni
Jon Uranga
Samuel Genheden
Ulf Ryde
Published in Journal of Chemical Information and Modeling
Volume 57
Pages 2865-2873
ISSN 1549-9596
Publication year 2017
Published at Department of Chemistry and Molecular Biology
Pages 2865-2873
Language en
Subject categories Theoretical Chemistry


We have investigated whether alchemical free-energy perturbation calculations of relative binding energies can be sped up by simulating a truncated protein. Previous studies with spherical nonperiodic systems showed that the number of simulated atoms could be reduced by a factor of 26 without affecting the calculated binding free energies by more than 0.5 kJ/mol on average (Genheden, S.; Ryde, U. J. Chem. Theory Comput. 2012, 8, 1449), leading to a 63-fold decrease in the time consumption. However, such simulations are rather slow, owing to the need of a large cutoff radius for the nonbonded interactions. Periodic simulations with the electrostatics treated by Ewald summation are much faster. Therefore, we have investigated if a similar speed-up can be obtained also for periodic simulations. Unfortunately, our results show that it is harder to truncate periodic systems and that the truncation errors are larger for these systems. In particular, residues need to be removed from the calculations, which means that atoms have to be restrained to avoid that they move in an unrealistic manner. The results strongly depend on the strength on this restraint. For the binding of seven ligands to dihydrofolate reductase and ten inhibitors of blood-clotting factor Xa, the best results are obtained with a small restraining force constant. However, the truncation errors were still significant (e.g., 1.5-2.9 kJ/mol at a truncation radius of 10 Å). Moreover, the gain in computer time was only modest. On the other hand, if the snapshots are truncated after the MD simulations, the truncation errors are small (below 0.9 kJ/mol even for a truncation radius of 10 Å). This indicates that postprocessing with a more accurate energy function (e.g., with quantum chemistry) on truncated snapshots may be a viable approach.

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