Re: Sudden /\A drop in last FEP window

From: Jérôme Hénin (jerome.henin_at_ibpc.fr)
Date: Fri Aug 17 2018 - 04:39:12 CDT

The end points are traditionally difficult to sample, but soft-core
potentials effectively displace this sampling problem from the end-points
towards the core of the lambda interval, allowing for more balanced
sampling. So it is not particularly surprising that you see a slower
convergence at a different lambda value, and that is all the more likely
that your soft-core shift is high.

Jerome

On Wed, 15 Aug 2018 at 06:44, Francesco Pietra <chiendarret_at_gmail.com>
wrote:

> Continuing the convergence check through forwd+back FEPs, I also obtained
> a "probability" for the 0.0-0.2 sector nearly as good as for the 0.8-1.0
> sector.
>
> Surprisingly, the "probability" for the 0.2-0.4 sector (forwd and back
> carried out with the same settings as for the other two sectors above, in
> particular with alchVdWShiftCoeff = 6.0) was bad, with separate gaussian
> throughout. I said 'surprisingly' as all suggestions are received, and
> guidelines I was able to find, remark the 0.0-0.2 sector as the most
> critical one. Really, contrary to such suggestions, in my case /\A
> increases by 18 for the 0.0-0.2 sector, and by 39 for the 0.2-0.4 sector.
>
> I would appreciate very much advice on this matter. Thanks
>
> francesco
>
> ---------- Forwarded message ---------
> From: Francesco Pietra <chiendarret_at_gmail.com>
> Date: Mon, Aug 6, 2018 at 4:30 PM
> Subject: Re: namd-l: Sudden /\A drop in last FEP window
> To: <jerome.henin_at_ibpc.fr>
> Cc: NAMD <namd-l_at_ks.uiuc.edu>
>
>
> Yes, you guessed correctly, quasi-convergence was not reached: frwd+back
> probability trace were, quasi, but not completely, superimposable.
>
> For the 0.8-1.0 sector of the five-sectors 0.0-1.0 plan, I have now
> obtained fine superimposition along 20 windows with many more fep steps,
> and /\A is now independent of flag variation.
>
> I am now going to complete the 0.0-0.2, by using the same approach for the
> other difficult sector 0.0-0.2. I am happy to be finally out of the
> trouble, however, the point is, the cost of FEP for a system of real
> biological interest. In this case of total 50,000 atoms, the 0.8-1.0
> sector, frw+back, required 38+38 real machine hours with 4 nodes, 144 core,
> along a special permission for longer that the standard 2hr. Because of
> limitation of scalability, there was no way to get quasi-convergence within
> 24hr, while the said special permission is difficult to obtain, now I got
> the permission until middle August for one FEP run at a time.
>
> thanks
> francesco
>
>
> On Sat, Jul 28, 2018 at 3:41 PM Jérôme Hénin <jerome.henin_at_ibpc.fr> wrote:
>
>> The value of alchVdWShiftCoeff should not change the actual (converged)
>> value of the free energy difference. Therefore at least one of these was
>> probably not well-converged. You can track convergence using tools like
>> ParseFEP.
>>
>> Jerome
>>
>> On Sat, 28 Jul 2018 at 12:30, Francesco Pietra <chiendarret_at_gmail.com>
>> wrote:
>>
>>> Hi Jerome:
>>> By only changing alchVdWShiftCoeff from 4.0 to 6.0, your expectation
>>> was fulfilled. The trend of /\A vs lambda was now smooth
>>>
>>> .....................
>>> ....................
>>> 0.9000/-12.4193
>>> 0.9100/-13.8066
>>> 0.9200/-15.0984
>>> 0.9300/-16.4011
>>> 0.9400/-17.5040
>>> 0.9500/-18.5221
>>> 0.9600/-19.5255
>>> 0.9700/-20.5133
>>> 0.9800/-21.4422
>>> 0.9900/-22.4359
>>> 1.0000/-23.6922
>>>
>>> I cannot detect any alarming sign in the simulation, in particular, the
>>> ligand remains undeformed and well in place throughout, not displaced, not
>>> rotated.
>>> Therefore, I am now perplexed at the value of /\A, differing by eight
>>> units from previous FEP with alchVdWShiftCoeff = 4.0.
>>> On the other hand, twenty windows for a small sector as 0.8-1.0 should
>>> not be too few.
>>>
>>> I would appreciate very much advice. Aas the change of alchVdWShiftCoeff
>>> from 4.0 to 6.0 too large?
>>>
>>> francesco
>>>
>>> ---------- Forwarded message ---------
>>> From: Francesco Pietra <chiendarret_at_gmail.com>
>>> Date: Fri, Jul 27, 2018 at 10:13 AM
>>> Subject: Fwd: namd-l: Sudden /\A drop in last FEP window
>>> To: <jerome.henin_at_ibpc.fr>, NAMD <namd-l_at_ks.uiuc.edu>
>>>
>>>
>>> On these basis I have resubmitted (on the queue) that FEP from scratch,
>>> by only changing alchVdWShiftCoeff from 4.0 to 6.0. We will see whether
>>> further changes, as you suggested, are necessary
>>>
>>> thanks
>>>
>>> francesco
>>>
>>> ---------- Forwarded message ---------
>>> From: Francesco Pietra <chiendarret_at_gmail.com>
>>> Date: Thu, Jul 26, 2018 at 7:54 PM
>>> Subject: Re: namd-l: Sudden /\A drop in last FEP window
>>> To: <jerome.henin_at_ibpc.fr>
>>> Cc: NAMD <namd-l_at_ks.uiuc.edu>
>>>
>>>
>>> Hi Jerome
>>> During my jogging I recognized to have missed the prot ocolin my mail. I
>>> was too late, anyway the protocol follows:
>>>
>>> outputenergies 1000
>>> outputtiming 1000
>>> outputpressure 1000
>>> restartfreq 1000
>>> XSTFreq 1000
>>> dcdFreq 5000
>>>
>>> hgroupcutoff 2.8
>>> switching on
>>> switchdist 10.0
>>> cutoff 12.0
>>> pairlistdist 14.0
>>>
>>> wrapAll on
>>>
>>> langevin on
>>> langevintemp 300.0
>>> langevindamping 2.0
>>>
>>> langevinpiston on
>>> langevinpistontarget 1
>>> langevinpistonperiod 100
>>> langevinpistondecay 100
>>> langevinpistontemp 300
>>> StrainRate 0.0 0.0 0.0
>>> useGroupPressure yes
>>>
>>> PME yes
>>> PMETolerance 10e-6
>>> PMEInterpOrder 4
>>> PMEGridSpacing 1
>>>
>>> timestep 0.5
>>> fullelectfrequency 2
>>> nonbondedfreq 1
>>>
>>> rigidbonds water
>>> stepspercycle 20
>>>
>>> alch on
>>> alchType FEP
>>> alchFile npt-15_frwd.fep
>>> alchCol B
>>> alchOutFile frwd-08.fepout
>>> alchOutFreq 50
>>>
>>> alchVdwLambdaEnd 1.0
>>> alchElecLambdaStart 0.5
>>> alchVdWShiftCoeff 4.0
>>> alchEquilSteps 100000
>>> set numSteps 400000
>>>
>>> runFEP 0.80 1.00 0.01 $numSteps
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>>
>>> On Thu, Jul 26, 2018 at 6:48 PM Jérôme Hénin <jerome.henin_at_ibpc.fr>
>>> wrote:
>>>
>>>> Hi,
>>>>
>>>> That is more or less an expected physical effect when the excluded
>>>> volume due to LJ repulsion disappears. In principle the soft-core
>>>> potentials were introduced to limit this effect (that is, to spread it over
>>>> a broader range of lambda and remove the singularity). You can try
>>>> experimenting with softer soft-core potentials by increasing the value
>>>> of alchVdwShiftCoeff from its default of 5 Å^2. Just note that the risk
>>>> with too much softening is to allow atoms of opposite charges to overlap,
>>>> which leads to an electrostatic catastrophe (singular Coulomb energy). So
>>>> the goal is to keep the barrier high enough that those clashes don't occur
>>>> as long as the Coulomb potential is nonzero. If you are using a protocol
>>>> that separates the contributions entirely, that is alchElecLambdaStart
>>>> >= alchVdwLambdaEnd, then there is no such risk and I suppose anything goes.
>>>>
>>>> Jerome
>>>>
>>>> On Thu, 26 Jul 2018 at 17:46, Francesco Pietra <chiendarret_at_gmail.com>
>>>> wrote:
>>>>
>>>>> Hello
>>>>> With every ligand-receptor FEP that I am carrying out with NAMD2.12, I
>>>>> noticed a sudden drop in the /\A values when when approaching lambda = 1.0,
>>>>> which seems to me prone to introducing large errors. I understand what
>>>>> happens in the system under such conditions, however i wonder whether the
>>>>> trend is out of the norm because I am missing some control.
>>>>>
>>>>> For example, for a ligand-receptor FEP divided into five sectors (in
>>>>> order to keep the calculations for each sector within 24hr), the
>>>>> ParseFEP.log for the 0.8-1.0 sector (lambda 0.01, 20 windows) reports
>>>>> lambda//\A
>>>>> ......................
>>>>> ....................
>>>>> 0.9000/1.2495
>>>>> 0.9100/1.2395
>>>>> 0.9200/1.1549
>>>>> 0.9300/1.0130
>>>>> 0.9400/0.6102
>>>>> 0.9500/-0.0087
>>>>> 0.9600/-1.8900
>>>>> 0.9700/-3.8335
>>>>> 0.9800/-6.8530
>>>>> 0.9900/-10.5326
>>>>> 1.0000/-15.9730
>>>>>
>>>>> Thanks for advice
>>>>> francesco pietra
>>>>>
>>>>

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