Re: convergence criterion of free energy perturbation (FEP) simulations for pKa calculation

From: Sadegh Faramarzi Ganjabad (safaramarziganjabad_at_mix.wvu.edu)
Date: Fri Oct 06 2017 - 14:04:39 CDT

Brian,

Thanks replying.
1) Regarding bonded terms, I thought they are already included; in the log
files I have these lines

FEP CURRENT LAMBDA VALUE 0
Info: FEP ELEC. ACTIVE FOR ANNIHILATED PARTICLES BETWEEN LAMBDA = 0 AND
LAMBDA = 0.5
Info: FEP ELEC. ACTIVE FOR EXNIHILATED PARTICLES BETWEEN LAMBDA = 0.5 AND
LAMBDA = 1
Info: FEP VDW ACTIVE FOR ANNIHILATED PARTICLES BETWEEN LAMBDA = 0 AND
LAMBDA = 1
Info: FEP VDW ACTIVE FOR EXNIHILATED PARTICLES BETWEEN LAMBDA = 0 AND
LAMBDA = 1
Info: FEP BOND ACTIVE FOR ANNIHILATED PARTICLES BETWEEN LAMBDA = 0 AND
LAMBDA = 1
Info: FEP BOND ACTIVE FOR EXNIHILATED PARTICLES BETWEEN LAMBDA = 0 AND
LAMBDA = 1

****
FEPTITLE: TS BOND2 ELECT2 VDW2
****
FEP: 0 22006.7270 -93162.0780 2413.1778
*****

If not, how could I include them?

2) How necessary it is to compute a difference in relative solvation free
energies?

3) Is there a way I could do study long time behavior of the BAR estimate
of the cumulative data with the ParseFEP plugin? I assume I should split
the entire simulation to smaller fractions?

Best,
Sadegh

On Thu, Oct 5, 2017 at 4:30 PM, Brian Radak <bradak_at_anl.gov> wrote:

> Does your transformation also include bonded terms? You will not compute a
> relative ionization free energy if you do not include those terms, although
> you can, in principle, compute a difference in relative solvation free
> energies by doing the corresponding calculation in the gas phase. I don't
> know your reasons for running your simulation, but I feel that I should
> point this out -- there are new keywords as of NAMD 2.11 for doing this
> (see the user guide).
>
> Agreement between the forward and backward FEP calculations is only a
> necessary condition for FEP convergence -- it is neither a sufficient
> condition for convergence nor a meaningful condition for other estimators,
> such as BAR.
>
> Another necessary, but still not sufficient, condition for convergence
> might be found in the long time behavior of the BAR estimate of the
> cumulative data (i.e. use the first 10 ns, then the first 20 ns, etc. and
> see if the answer changes as the simulation gets longer).
>
> The forward and backward construction loses all meaning when analyzing
> with thermodynamic integration, for the same reason as it does for BAR.
>
> HTH,
> Brian
>
> On 10/05/2017 02:36 PM, Sadegh Faramarzi Ganjabad wrote:
>
>> Hello,
>>
>> I am running a test FEP simulation to calculate free energy of the
>> ionization of an amino acid inside a membrane protein. Here is the FEP part
>> of my namd config.
>>
>> source ../tools/fep.tcl
>>
>> alch on
>> alchType FEP
>> alchFile all-ion-beta.pdb
>> alchCol B
>> alchOutFile forward-shift-pr.fepout
>> alchOutFreq 10
>> alchBondDecouple on
>> alchBondLambdaEnd 1.0
>>
>> alchVdwLambdaEnd 1.0
>> alchElecLambdaStart 0.5 #soft potential
>> alchVdWShiftCoeff 6.0
>> #alchDecouple off
>>
>> alchEquilSteps 100
>> set numSteps 500
>>
>> runFEPmin 0.0 1.0 0.0625 10000 1000 310
>>
>> Then I used ParseFEP of VMD. The difference between DeltaG of the forward
>> and backward transformation is about 5 kcal/mol for lambda=0 to 0.5, and it
>> become almost 0 for lambda = 0.6 to 1. I should probably increase
>> simulation time for each lambda from 10,000 to say 10,000,000 until the
>> plots of forward and backward lie on top of each other. My question is that
>> is this the only criterion for convergence of FEP calculation? How can I
>> make sure my simulation is long enough?
>>
>> Also, if I use thermodynamic integration method for free energy
>> calculations, what would be convergence criteria for that?
>>
>> Thanks,
>> Sadegh
>>
>>
> --
> Brian Radak
> Postdoctoral Appointee
> Leadership Computing Facility
> Argonne National Laboratory
>
> 9700 South Cass Avenue, Bldg. 240
> Argonne, IL 60439-4854
> (630) 252-8643
> brian.radak_at_anl.gov
>

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