[gmx-developers] constraints and BAR free energy

[Floris Buelens]

Hello,

I have a question about the perturbation of constraints. My understanding is 
that dv/dlambda is easily calculated for constraints, so that constraint 
perturbation is fine for thermodynamic integration - but that calculating the 
deltaV to another lambda value as required for e.g. BAR doesn't make sense or 
isn't practical. Here's the relevant comment in force.c:

/* Notes on the foreign lambda free energy difference evaluation:
 * Adding the potential and ekin terms that depend linearly on lambda
 * as delta lam * dvdl to the energy differences is exact.
 * For the constraint dvdl this is not exact, but we have no other option.
 */

So far I've always avoided perturbing constraints but I now need to recalculate 
some results based on topologies with a ring-bound hydrogen mutating to a methyl 
group. Is there an exact way to do this in gromacs using BAR?

More generally I'd be concerned about the accuracy of the linear extrapolation 
of constraint dv/dl - depending on how you set out your transformation pathway I 
would imagine you could end up skipping over a lot of detail in exactly this 
kind of situation where a methyl group is 'pushing' out from a hydrogen.

Best wishes,

Floris