[gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I am getting the same following warning even after minimizing the system twice using cg integrator. This is only when the free energy stuff is inserted in the energy minimization code.

" WARNING: Listed nonbonded interaction between particles 2263 and 2298 at distance 3f which is larger than the table limit 3f nm.

This is likely either a 1,4 interaction, or a listed interaction inside a smaller molecule you are decoupling during a free energy calculation. Since interactions at distances beyond the table cannot be computed, they are skipped until they are inside the table limit again. You will only see this message once, even if it occurs for several interactions.

IMPORTANT: This should not happen in a stable simulation, so there is probably something wrong with your system. Only change the table-extension distance in the mdp file if you are really sure that is the reason. "


When the system is minimized without free energy code, it shows no warning. Hence, I suppose it is due to the free energy code itself with couple-intramol = no.

I found the warning disappears when couple-intramol = yes. But this is not I would like to do, since intra molecular interactions need not be scaled/perturbed.

It's definitely true that the "listed interaction inside a smaller molecule you are decoupling during a free energy calculation". 

When the table-extension is increased to 4 nm with couple-intramol = no, the warning again disappears. Should I go forward with this setting and how will it affect the energy minimization of my system?

Best Regards,
Bhagyesh

----- Original Message -----
From: "Justin Lemkul" <jalemkul at vt.edu>
To: gmx-users at gromacs.org
Sent: Wednesday, June 28, 2017 7:17:34 AM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

On 6/27/17 7:43 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> When the system is minimized with full interactions with no free energy code, I see no warnings and the systems is minimized properly.
> 
> However, when the free energy code is added with couple-intramol = no, I encounter the said warning, but still the system can be minimized ignoring the warning.
> 
> When the free energy code is added with couple-intramol = yes, there's no warning, but the system is again well minimized.
> 

You may need several rounds of energy minimization to get a stable result.  Your 
final minimization and equilibration should be done under the 
conditions/settings that make the most sense for you to model.

-Justin

> I would like to learn if its reasonable to ignore the warning in the case where couple-intramol = no, since I am dealing with a peptide and intramolecular interactions can suppress the intermolecular interactions.
> 
> I intend to perform normal-mode calculations on the resulting intermediates which are divergent from the Binding energy simulations requiring convergence. Hence, I presume there shouldn't be much complication in this case. I understand the approach seems quite outlandish, but still I aspire to execute the same. Any opinions and/or suggestions in this procedure will be greatly helpful.
> 
> Many thanks,
> 
> Bhagyesh.
> 
> 
> ----- Original Message -----
> From: "Justin Lemkul" <jalemkul at vt.edu>
> To: gmx-users at gromacs.org
> Sent: Tuesday, June 27, 2017 6:42:33 PM
> Subject: Re: [gmx-users] Doubt about Free Energy control Minimization
> 
> On 6/26/17 9:09 AM, Varvdekar Bhagyesh Rajendra wrote:
>> Dear Justin,
>>
>> I have encountered the following warning when I used the following code to minimize my protein-ligand system when the interaction potential energy between the protein and the ligand are multiplied by 0.9, 0.8, 0.7,..., 0.2, 0.1.
>>
>> http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp
>>
>> Warning: 1-4 interaction between 2263 and 2298 at distance 1.004 which is larger than the 1-4 table size 1.000 nm
>> These are ignored for the rest of the simulation
>> This usually means your system is exploding,
>> if not, you should increase table-extension in your mdp file
>> or with user tables increase the table size
>>
>>
>> I suppose this error is due to setting couple-intramol = no. When it is set to yes, the warning vanishes.
>>
>> But, this is my desired setting since, I do not intend to scale the intra molecular interactions even though the ligand is a peptide. Is it reasonable to ignore the warning. If not , how can it affect my resulting structure ? And are all such interaction "ignored for the rest of the simulation" ?
>>
> 
> So the system is unstable.  Try minimizing with full interactions before doing
> anything funny with scaling.  And I repeat my caution to you that trying to do
> an alchemical transformation of a peptide is a very unwise choice.  You'll never
> get the simulations to converge in a practical amount of time.
> 
> -Justin
> 

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

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

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