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Changes in how Amber handles softcore interactions (August, 2019)

What was changed

In August, 2019, we posted to two significant updates to how Amber handles softcore interactions in free energy calculations: these were AmberTools19 update.8 (for sander) and Amber18 update.15 (for pmemd).

To install these changes, do the following, then recompile:

$AMBERHOME/update_amber --update

Before the update, if one had 1-4 electrostatic or Lennard-Jones interactions that connected one atom in a softcore region with another atom in a "fixed" (non-softcore) region, that interaction was made to be independent of lambda, and hence did not contribute to dV/dlambda in the free energy calculation. After the update, such terms are handled in the "standard" way, that is, the interaction strength is dependent on lambda

Basically, the error arose from incorrectly using "and" instead of "or" in a logical statement examining 1-4 interactions. See the changes to amber18/AmberTools/src/sander/extra_pts.F90 in AmberTools19 update.8 or to amber18/src/pmemd/src/extra_pnts_nb14.i in Amber18 update.15. Thanks to Taisung Lee, Darrin York, Charlie Lin and David Case for working on the patch.

Our attention to this issue was driven by internal testing (to be reported elsewhere) and by reports from users, including results of Loeffler et al., J. Chem. Theory Comput. 14, 5567 (2018).

What the likely effects are

  1. If your free energy calculation doesn't use the softcore option (ifsc=1), then nothing will change.

  2. If your softcore region doesn't have any covalent connections to a non-softcore region, then nothing should change.

  3. If your softcore region does have a covalent connection to a non-softcore region, you should expect to see potentially significant changes in delta-G values along a particular leg of a thermodynamic cycle; however, differences between "unified" calculations (where both LJ and electrostatic energies are removed in a softcore step) and "split" protocols (where electrostatic energies are treated in separate, non-softcore steps) should go away.

    You may also see changes in delta-delta-G values, i.e. the difference between two legs of a thermodynamic cycle, and the only value that can be compared to experiment. There are circumstances in which the changes may be small:

    • For fairly rigid systems, where the conformational ensemble on one leg of the thermodynamic cycle is nearly the same as on the other leg, the changes imposed by these updates will nearly cancel on the two legs of the cycle, leading to only small changes in delta-delta-G.

    • If the softcore region has zero charges, as would be the case when charges are removed in an earlier step, the remaining 1-4 Lennard-Jones interactions are often quite small, again leading to only small changes in delta-delta-G.

  4. These updates do not address all possible problems with softcore calculations. Basically, the Amber codes allow one to choose any softcore region one likes, without taking into account the nature of the covalent interactions (if any) between softcore and non-softcore regions. This actually works pretty well in a large number of cases, but does not guarantee provide proper end-states for free energy calculations. Work is ongoing on how to achieve both a reliable and intuitive way to compute alchemical free energies when some atoms are present in one end state but not in the other.

    In particular, the softcore scheme as currently implemented in Amber may fail badly if you have a softcore region that is connected to a common (non-softcore) region by more than one covalent bond. Even with just one bond to the softcore region, you may see significant effects if the conformations of the softcore region sampled on one leg of the thermodynamic cycle are significantly different from those on the other leg. Problems can also arise if the size of a softcore region is larger than the cutoff value for non-bonded interactions.

"How's that for maxed out?"

Last modified: May 3, 2020