[gmx-developers] constraints and BAR free energy

[hess at sbc.su.se]

Well, the integration error is the whole thing.
BAR is significantly better than free energy integration
and it is unbiased.

We are thinking about doing BAR properly with constraints,
but that's not trivial.

Berk

> What's the approximation for case 1), apart of course from the integration
> error? Isn't it just an analytical derivative dV/dl?
> Agreed that in most normal cases the error for case 2) should be small but
> my
> superstition against perturbing constraints does seem somewhat justified,
> especially since in most cases with 2fs time steps it can be avoided by
> not
> mutating hydrogen to non-hydrogen...
> thanks!
>
> Floris
>
>
>
>
> ----- Original Message ----
> From: "hess at sbc.su.se" <hess at sbc.su.se>
> To: Discussion list for GROMACS development <gmx-developers at gromacs.org>
> Sent: Wed, 20 October, 2010 11:03:51
> Subject: Re: [gmx-developers] constraints and BAR free energy
>
> Hi,
>
> Strictly speaking BAR is impossible with changing constraint lengths.
> Since the constrained distances are different for different lambda's,
> the ensembles never overlap.
>
> So there are two options:
> 1) I forget about BAR and do free energy integration
> 2) I use Delta_lambda*dV/dlambda for the constraint contribution
>
> 1) Has the same "approximation" for the contraints as 2) and additionally
> has larger and systematic errors. So I would go for 2).
>
> In most situations constraint lengths change very little between
> adjacent lambda points, so 2) should be a very good approximation.
>
> Berk
>
>> 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
>>
>>
>>
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