Can System Truncation Speed up LigandBinding Calculations with Periodic FreeEnergy Simulations?
(2017) In Journal of Chemical Information and Modeling 57(11). p.28652873 Abstract
We have investigated whether alchemical freeenergy 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 63fold 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... (More)
We have investigated whether alchemical freeenergy 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 63fold 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 speedup 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 bloodclotting factor Xa, the best results are obtained with a small restraining force constant. However, the truncation errors were still significant (e.g., 1.52.9 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.
(Less)
 author
 Manzoni, Francesco ^{LU} ; Uranga, Jon; Genheden, Samuel ^{LU} and Ryde, Ulf ^{LU}
 organization
 publishing date
 20171127
 type
 Contribution to journal
 publication status
 published
 subject
 in
 Journal of Chemical Information and Modeling
 volume
 57
 issue
 11
 pages
 9 pages
 publisher
 The American Chemical Society
 external identifiers

 scopus:85035352540
 wos:000416614900022
 ISSN
 15499596
 DOI
 10.1021/acs.jcim.7b00324
 language
 English
 LU publication?
 yes
 id
 23b96a45b5e244489f132891130ff718
 date added to LUP
 20171212 13:12:53
 date last changed
 20180501 23:24:26
@article{23b96a45b5e244489f132891130ff718, abstract = {<p>We have investigated whether alchemical freeenergy 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 63fold 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 speedup 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 bloodclotting factor Xa, the best results are obtained with a small restraining force constant. However, the truncation errors were still significant (e.g., 1.52.9 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.</p>}, author = {Manzoni, Francesco and Uranga, Jon and Genheden, Samuel and Ryde, Ulf}, issn = {15499596}, language = {eng}, month = {11}, number = {11}, pages = {28652873}, publisher = {The American Chemical Society}, series = {Journal of Chemical Information and Modeling}, title = {Can System Truncation Speed up LigandBinding Calculations with Periodic FreeEnergy Simulations?}, url = {http://dx.doi.org/10.1021/acs.jcim.7b00324}, volume = {57}, year = {2017}, }