[gmx-users] Free energy in octanol and water

[Justin Lemkul]

On 9/29/15 4:51 AM, Gmx QA wrote:
> Hi gmx-users
>
> I am trying to calculate the free energy of solvation for a drug-molecule
> in octanol and water.
>
> I am comparing two situations:
>
> A: Two systems, one with the drug in water only, and one with the drug in
> pure octanol.
>
> B: drug in water only (same as in A), and then one box where I have added
> 20% water to my octanol system (since mixtures of octanol and water
> typically contains some water in the octanol phase).
>
> Then I run a series of free energy calculations per Justin's tutorial, 48
> lambda points in total.
> For system A I get a Delta-G for pure water of 39.07 kJ/mol, and 92.81
> kJ/mol in pure octanol.
>
> For system B, the Delta-G for pure water is the same, but for the
> octanol-box with 20% water the Delta-G is 95.99 kJ/mol.
>
> All of these results are obtained using gmx bar in gromacs 5.0.4.
>
> My main concern is that the Delta-G is higher in the water/octanol mixture
> than in pure octanol, but I would have expected the reverse to be the case?
>

 From experience, I can tell you it is very hard to get good convergence on such 
mixtures.  You'll note that in npt.gro you effectively have two bands of water 
formed in the box, neither or which is particularly close to the API molecule. 
You'll probably get some microscopic phase separation.  The route I've gone in 
the past is to generate several starting configurations (different random seeds 
when inserting the water molecules) and averaging over multiple runs.  You 
should also do some error analysis of your results (both block averaging for 
convergence, and to compare the two DG values between the systems).  Without 
error bars, you have no idea if those two values are at all meaningfully different.

-Justin

> Is there something wrong with my protocol? The forcefield is
> GAFF/amber99sb,and all production runs are 10 ns in length.
>
> Best
> /PK
>
> I have uploaded copies of all input-files here:
>
> https://dl.dropboxusercontent.com/u/66785227/md.mdp
> https://dl.dropboxusercontent.com/u/66785227/npt.gro
> https://dl.dropboxusercontent.com/u/66785227/octanol_GMX.itp
> https://dl.dropboxusercontent.com/u/66785227/API_gmx.itp
> https://dl.dropboxusercontent.com/u/66785227/topol.top
>

-- 
==================================================

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalemkul at outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==================================================