Hi Thomas,
Thanks for the suggestion!
I just tried running igb=0 with pmemd on CPU and it worked fine. So maybe
it's something wrong with CUDA?
I think you are right that I don't have a fully closed thermodynamic cycle.
I came up with an equation, like ddG(wt to mutant, in solvent, from
TI)=ddG(wt to mutant, gas phase, from TI)+ddG(difference of mutant
solvation energy and wild type solvation energy, from MM/GBSA). But it
seems like not accessible.
I'll try the alchemical ion approach again.
Thanks,
Fanyu
On Mon, Jun 5, 2023 at 4:02 PM Steinbrecher, Thomas <
thomas.steinbrecher.roche.com> wrote:
> Hi Fanyu,
>
> sorry to hear igb=0 didnt work, but have you checked running the same job
> using pmemd or sander on CPU? If it segfaults there as well, it likely is
> something about the input you are using. If you want to make sure the
> charge change is the source of the problem, could you try the same
> calculation with a protonated Asp, just to check your input (plus one H)
> works in that case?
>
> I still dont understand what you need the vacuum simulation for, if this
> is about peptide binding, then you would normally simulate the peptide
> transformation in solvent and bound to whatever it is binding to. A vacuum
> TI transformation is only needed if you care about the change in solvation
> free energy (from ddG(TI,solv) - ddG(TI,vac) ) and since that is probably
> not something experimentally accessible for a peptide, what would you use
> the result for?
>
> If you really care about this transformation in vacuum, it may be hard to
> get a meaningful answer. Changing a charge in vacuum is not the same as
> changing it in a periodic boundary environment, due to the charge-charge
> interactions between periodic images, so your thermodynamic cycle doesnt
> quite close. I'm not 100% sure what the current best practice is to handle
> such cases, but the alchemical ion approach is intended to get rid of such
> box size effects. Since the alchemical ion approach does not work in
> vacuum, Id stear clear of total system charge changes for such a case.
>
> Kind Regards,
>
> Thomas
>
> On Mon, Jun 5, 2023 at 9:42 AM Fanyu Zhao <fz2113.nyu.edu> wrote:
>
>> Hi Thomas,
>>
>> Thanks for your reply!
>>
>> Yes, I tried using igb=0, and the simulation just stopped at reading
>> restart file. The error message gives a segmentation fault so I think there
>> might be something wrong with the input file I'm using.
>>
>> Actually, I'm trying to calculate the relative binding free energy of a
>> peptide mutation involving charge-changing (e.g. mutating Asp to Ala, with
>> the charge changing from -1 to 0). So far I've tried using co-alchemical
>> ions to balance the charge between the two systems, or running the
>> simulation without any correction of the changed charge. Both failed.
>>
>> So I'm thinking if I could firstly calculate the energy change of
>> mutation on gas phase, and secondly calculate the solvation energy
>> difference of the wild-type and mutant, and then sum the two terms up.
>>
>> I cannot figure out any other methods in TI to calculate the mutation
>> involving charge-changing :(. It would be appreciated if you could give me
>> any suggestions on this.
>>
>> Best,
>> Fanyu
>>
>> On Mon, Jun 5, 2023 at 3:29 PM Steinbrecher, Thomas <
>> thomas.steinbrecher.roche.com> wrote:
>>
>>> Hi Fanyu,
>>>
>>> have you tried running with igb = 0 ? It should be the same effect as
>>> igb=6 based on what I see in the manual, but maybe there is a check in
>>> pmemd about "igb > 0" that is missing that igb = 6 would also correspond to
>>> vacuum?
>>>
>>> As a side note, based on the masks, you seem to have a 10+ residue
>>> peptide in your simulation, are you sure a vacuum simulation of this
>>> species is meaningful?
>>>
>>> Kind Regards,
>>>
>>> Thomas
>>>
>>> On Mon, Jun 5, 2023 at 4:26 AM Fanyu Zhao via AMBER <amber.ambermd.org>
>>> wrote:
>>>
>>>> Dear amber users,
>>>>
>>>> I'm trying to run TI in the gas phase. But it always gives me an error
>>>> message of "The CUDA code currently cannot handle TI with implicit
>>>> solvent
>>>> models! Please use the serial code instead".
>>>>
>>>> I was wondering if gas phase TI can only be performed with CPU and if
>>>> I'm
>>>> correct with the process of creating a pdb file in gas phase.
>>>>
>>>> Here's my input for a minimization.
>>>>
>>>> Minimization with position restraint
>>>> &cntrl
>>>> imin = 1, ntmin = 2, maxcyc = 10000,
>>>> ntpr = 1000, ntwe = 1000,
>>>> ntr = 1, restraint_wt = 100.0,
>>>> restraintmask = '!.H= ',
>>>> ntb=0,igb=6, cut = 9999.0, ioutfm = 1,
>>>> icfe = 1, ifsc = 1, logdvdl = 0,
>>>> timask1=':10',
>>>> timask2=':3',
>>>> scmask1=':10 & !.CA,C,N,O',
>>>> scmask2=':3 & !.CA,C,N,O',
>>>> clambda=0.5,
>>>> &end
>>>> /
>>>>
>>>>
>>>> And here's the tleap file I used to generate a gas phase pdb file.
>>>>
>>>> source leaprc.protein.ff14SB
>>>>
>>>> com=loadpdb 1tvb_aftermd.pdb
>>>> unbound=loadpdb peptide.pdb
>>>>
>>>> savepdb com wild_md_bound.pdb
>>>> saveamberparm com wild_md_bound.prmtop wild_md_bound.inpcrd
>>>>
>>>> savepdb unbound wild_md_unbound.pdb
>>>> saveamberparm unbound wild_md_unbound.prmtop wild_md_unbound.inpcrd
>>>> quit
>>>>
>>>>
>>>> Thank you so much!
>>>>
>>>> Best,
>>>> Fanyu
>>>> _______________________________________________
>>>> AMBER mailing list
>>>> AMBER.ambermd.org
>>>> http://lists.ambermd.org/mailman/listinfo/amber
>>>> <https://urldefense.proofpoint.com/v2/url?u=http-3A__lists.ambermd.org_mailman_listinfo_amber&d=DwMFaQ&c=slrrB7dE8n7gBJbeO0g-IQ&r=TA6Yv1GqGslhLaifgggoUQ&m=4WjHVK2ypm7vH0Okye8p2Ny0JAsKRcIz9NXV9bVSYGgs24GTPqJvmd0_PYIvgSFY&s=jj3P4Wq5mxqWq6hYdbE91qLTi7Stm6DKikZPbRtmspw&e=>
>>>>
>>>
>>>
>>> --
>>> *Dr. Thomas Steinbrecher*
>>> Principal Scientist CADD
>>>
>>> Roche Pharma Research and Early Development
>>> Roche Innovation Center Basel
>>> F. Hoffmann-La Roche Ltd
>>> Bldg. 092/3.92
>>> Grenzacherstrasse 124
>>> 4070 Basel
>>> Switzerland
>>>
>>> Phone +41 61 682 1319
>>> mailto: thomas.steinbrecher.roche.com
>>>
>>
>
> --
> *Dr. Thomas Steinbrecher*
> Principal Scientist CADD
>
> Roche Pharma Research and Early Development
> Roche Innovation Center Basel
> F. Hoffmann-La Roche Ltd
> Bldg. 092/3.92
> Grenzacherstrasse 124
> 4070 Basel
> Switzerland
>
> Phone +41 61 682 1319
> mailto: thomas.steinbrecher.roche.com
>
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Received on Mon Jun 05 2023 - 02:00:02 PDT
