Bob, > When performing a relative binding free energy calculation, I > understand that it is a good practice to separate the transformation > of charges of the ligand and the transformation of vdW parameters into > two calculations. However, is it advisable to completely discharge the > ligand before transforming vdW parameters? For example, should the > calculation proceed as: > 1. Reduce all ligand charges to zero > 2. Transform vdW parameters for relevant atoms > 3. Recharge ligand atoms with the new, appropriate values
As far as I am aware there hasn't been a lot of testing here on what's most efficient. What I've been doing in some relative free energy studies lately (which I think is a good idea) is to (1) turn all ligand charges on atoms which will be inserted/deleted to zero, while simultaneously changing the charges on any atoms which will undergo charge modifications; (2) transform vdw parameters for relevant atoms; then (3) restore ligand charges on any atoms which have been inserted. Alternatively the modification of charges on changed atoms can be done in step (3). > It seems to me that steps 1 and 3 would yield large free energy > changes, thus making the calculation of free energy differences > between the bound and unbound states more difficult due to convergence > issues. That could be true. On the other hand, my experience with electrostatic transformations is that it's possible to compute these quite precisely even if the values are extremely large. That is, I don't see the magnitude of the uncertainty scaling with the magnitude of the total. So it might be possible to do this very precisely. Still, I don't see any reason to change charges on atoms that you aren't going to be modifying at all. > Is it more advisable to proceed as: > 1. Reduce charges to zero on ONLY those ligand atoms that will have > their vdW parameters transformed > 2. Transform vdW parameters for relevant atoms > 3. Transform charges on ligand to their new, appropriate values Yes, that sounds better. Where I woudl worry about convergence is not so much in the magnitude of the charging free energies, but rather that if you're turning off all the charges on something, the conformational ensembles it will sample may be quite different from those it would sample with its charges on. It's probably best to perturb the ensemble as little as possible unless you have some reason to believe that perturbing the ensemble will improve your sampling. David > > Proceeding in this way seems like you would obtain smaller free energy > changes for steps 1 and 3 and could result in better convergence for > free energy differences. Any suggestions? > > Thanks, > Bob > _______________________________________________ > gmx-users mailing list gmx-users@gromacs.org > http://www.gromacs.org/mailman/listinfo/gmx-users > Please search the archive at http://www.gromacs.org/search before posting! > Please don't post (un)subscribe requests to the list. Use the > www interface or send it to [EMAIL PROTECTED] > Can't post? Read http://www.gromacs.org/mailing_lists/users.php > _______________________________________________ gmx-users mailing list gmx-users@gromacs.org http://www.gromacs.org/mailman/listinfo/gmx-users Please search the archive at http://www.gromacs.org/search before posting! Please don't post (un)subscribe requests to the list. Use the www interface or send it to [EMAIL PROTECTED] Can't post? Read http://www.gromacs.org/mailing_lists/users.php
