AMBER Archive (2005)

Subject: Re: AMBER: TI-FEP for VAL --> ALA

From: Jiten (jiten_at_postech.ac.kr)
Date: Sun Jun 26 2005 - 21:11:03 CDT

Hi Ilyas Yildirim,

Thax for your mails. A year back when I start learning TI-FEP, there was no
proper tutorials by then. Therefore, there is something wrong with the set
up of my system. I looked to the amber tutorial on Thermodynamic
Intergration method which was written by D. Case somtime in Jan 2005 - it is
really helpful.

Thanks,

Jiten

----- Original Message -----
From: "Ilyas Yildirim" <yildirim_at_pas.rochester.edu>
To: <amber_at_scripps.edu>
Sent: Sunday, June 26, 2005 8:39 AM
Subject: Re: AMBER: TI-FEP for VAL --> ALA

> Hey Jiten,
>
> On Sun, 26 Jun 2005, Jiten wrote:
>
>> Hi Ilyas Yildirim,
>>
>> Thanks for the reply. First of all I apologize, what I have got zero
>> difference is of V--> A TI-FEP. The frcmod.DH was constructed as give
>> before
>> for ALA-->GLY.
>
> I assume by TI-FEP u mean free energy calculation using Thermodynamic
> Integration approach.
>
>>
>> First - I do not understand why I need use hydrogen mass for dummy atom.
>> Second - I think that if I put the force constant and eq distance/angle
>> for
>> the dummy atoms, with that just replaced by that off
>> !CT-HC, !HC-CT-HC,!HC-CT-HC etc -- I am confused if it still be alright?
>>
>
> In the TI Approach tutorial, the dummy atoms had some mass. I think the
> reason is because of the mixed (hybrid) Hamiltonian. The forces are
> calculated according to this Hamiltonian. A zero mass might give an error,
> I think. The best choice is to use the mass of DH as
>
> MASS
> DH 1.008
>
> If it was a transformation from C->DC (dummy Carbon), it is better to use
> the mass of carbon for the mass of DC.
>
> For the second part of the question: I would do the same; defining the
> missing parameters by making some analogies with the old structure. In
> your case you have to define one more parameter, which is the dihedral
> angle of
>
> X -CT-HO-X
>
> Now, the reason why you have to have these force constants is to keep the
> structure in shape. The question is: Are these extra dummy atom parameters
> going to change the energy of the system? Yes they will but I do not think
> this is that crucial. These parameters are going to give some extra
> internal energy to the system, namely energy coming
> because of bonded parameters. In order to compare this free energy change
> with an experimental data, you have to do another free energy change
> simulation in gas phase (assuming you have done the first simulation in
> water). And then, u will subtract these 2 results. These internal/bonded
> energies will cancel at the end. So, that result will give you some
> reasonable prediction which can be compared with an experimental data.
>
> Here is what I mean:
>
> C-(H)3 ------------------> H-(DH)3
> (in water) G3 (in water)
> /\ /\
> || ||
> || ||
> || ||
> || G1 G2 ||
> || ||
> || ||
> || G4 ||
> C-(H)3 ------------------> H-(DH)3
> (in gas) (in gas)
>
> G1 and G2 are the experimental results, which are the solvation free
> energies. G3 and G4 are supposed to be the free energy simulation results.
> So,
>
> G1 - G2 = G3 - G4
>
> What I mean is, you have to do two free energy calculation, one for the
> solvated case, one in gas phase in order to compare it with an
> experimental result.
>
>> Also, I expect that the total energy after 12 windows be lower than the
>> first window (similar to that of MM-PBSA), but they are not as given
>> below.
>> The structure after 12th window is still alright - nothing unusual.
>> Therefore, I feel that there something very wrong with it.
>>
>> Amber TI-FEP expert would help me ???
>>
>> MM-PBSA A V
>> ELE -8.44 -8.02
>> VDW -36.38 -36.02
>> GAS -44.82 -44.04
>> PBSUR -3.14 -3.01
>> PBCAL 23.04 24.59
>> PBSOL 19.91 21.58
>> PBELE 14.61 16.58
>> PBTOT -24.91 -22.46
>> TSTOT 18.48 17.58
>> PBTOT-S -6.43 -4.88
>>
>>
>> This is in good agreement with experiment.
>>
>> From first window,
>>
>> A V E R A G E S O V E R 50000 S T E P S
>>
>>
>> NSTEP = 100000 TIME(PS) = 120.000 TEMP(K) = 299.17 PRESS =
>> 0.0
>> Etot = -77963.7518 EKtot = 19966.8759 EPtot
>> = -97930.6277
>> BOND = 722.3367 ANGLE = 1873.6537 DIHED =
>> 2212.5509
>> 1-4 NB = 935.9809 1-4 EEL = 11755.7341 VDWAALS =
>> 11246.8856
>> EELEC = -126677.7697 EHBOND = 0.0000 RESTRAINT =
>> 0.0000
>> DV/DL = 768.0586
>> Ewald error estimate: 0.6501E-04
>> ------------------------------------------------------------------------------From
>> 12th window, A V E R A G E S O V E R 50000 S T E P S NSTEP =
>> 100000 TIME(PS) = 1440.000 TEMP(K) = 299.59 PRESS =0.0 Etot
>> -77806.2969 EKtot = 19994.8561 EPtot = -97801.1530 BOND
>> = 712.4664 ANGLE = 1866.1103 DIHED =2207.5175 1-4 NB
>> = 933.9198 1-4 EEL = 11775.2910 VDWAALS =11186.6417 EELEC
>> = -126483.0998 EHBOND = 0.0000 RESTRAINT =0.0000 DV/DL =
>> 0.0000 Ewald error estimate:
>> 0.6711E-04 ------------------------------------------------------------------------------The
>> dV/dl are as follows, 1 2 3 4 5 6 7 8 9 10 11 12 lam(i)
>> 0.00922 0.04794 0.11505 0.20634 0.31608 0.43738 0.562620.68392 0.79366
>> 0.88495 0.95206 0.99078 w(i) 0.02359 0.05347 0.08004 0.10158
>> 0.11675 0.12457 0.12457 0.116750.10158 0.08004 0.05347 0.02359
>> 768.05860 361.0522012.45120 -118.71170 -113.01570 -65.58740 -2
> 8!
>> .53030 -10.29490 -2.07680 -0.17480 -0.00800 0.00000 Total 18.11850
>> 19.305460.99659 -12.05873 -13.19458 -8.17022 -3.55402 -1.20193 -0.21096 -0.01399
>> -0.00043 0.00000 0.01569Sincerely,Jiten----- Original Message -----From:
>> "Ilyas Yildirim" <yildirim_at_pas.rochester.edu>To: <amber_at_scripps.edu>Sent:
>> Saturday, June 25, 2005 3:48 PMSubject: Re: AMBER: TI-FEP for ALA -->
>> GLY> Hi Jiten,>> The frcmod file u created looks ok, but why do u have 0
>> mass on the dummy> atoms? I would have chosen the hydrogen mass rather
>> than a zero mass for> the DH atom.>> Second thing, did u check out one of
>> the trajectory file to see if> everything is ok? And also, what are your
>> dv/dl results for these 12> lambda values. I have done a simple free
>> energy calculation for> ethane->methane which looks similar to what you
>> have done (-CH3 changes to> H-DH3). I also got a result which was close
>> to zero. I did the simulation> just for a test purpose. I have used
>> explicit solvent. In order to compare> with s
> o!
>> mething real (with an experimental data), u have to do 2 different> TI
>> simulation: One in a solvent, the other in gas phase, and take the>
>> difference of these results. That will give u a prediction for an>
>> observable. (Thermodynamic Cycle)>> For the ethane->methane case, the
>> solvation of ethane and methane are> almost the same, so it is reasonable
>> to expect something close to zero.> What is the solvation free energies
>> of ALA and GLY (or the solvation free> energies of the initial and final
>> states of your system)? The difference> of these energies should be equal
>> to the free energy change of the> transformation in a solvent subtracted
>> from the free energy change of the> transformation in gas phase.>> Good
>> luck,>> On Sat, 25 Jun 2005, Jiten wrote:>>> Dear Amber users>>>> For my
>> protein-drug system : while doing the free energy peturbationusing TI
>> method using 12 windows, and using the perl script attached here, Igot
>> almost zero difference in free energy. I used the following atom
>> types,where DH is dummy atom with zero charge and the charges of
> t!
>> he alaline isreplaced by glycine charges in the pert.charge
>> options>>>>>> H1 HC H0 DH>> | |
>> | |>> --CT---CT--HC ---> --CT --H0--DH>> |
>> |>> HC DH>>>> My frcmod.DH is as
>> follows,>>>> ALA to GLY>> MASS>> DH 0.000>>>> BOND>> H0-DH
>> 340.0 1.090 !CT-HC>>>> ANGLE>> DH - H0 - DH 35.0 109.50
>> !HC-CT-HC>> CT - H0 - DH 35.0 109.50 !HC-CT-HC>>>>
>> DIHE>> - The default values as given by leap>> -->> -->>>> NONB>> DH
>> 0.000 0.00>>>> Am I doing something stupid here ? Do I need to set the
>> Bond and angles :K and R values as zero ?>>>> However, I calculate the
>> absolute free energy of the two syatems usingMM-PBSA from the last 1ns
>> trajectory of the 2ns MD simulations (wellconverged - rmsd, temp and
>> energy) and I got that there is clear differencesbetween the two protein
>> systems.
> >!
>> >>> ELE -8.99 -8.96>> VDW -41.125 -37.68>> GAS
>> -50.115 -46.64>> PBSUR -3.025 -3.07>> PBCAL 27.105
>> 24.16>> PBSOL 24.09 21.09>> PBELE 18.12 15.2>>
>> PBTOT -26.025 -25.55>> TSTOT 12.675 15.79>>
>> PBTOT-S -13.35 -9.76>>>>>> Thanks for any suggestions,>>>>
>> Sincerely,>>>> N. Jiten Singh>> C/O Prof. Kwang S. Kim>> Department of
>> Chemistry>> Pohang University of Science and Technology>> San 31,
>> Hyojadong, Namgu>> Pohang 790-784, Korea>> Phone : 82-54-279-5853 ( Lab )
>> / 279-4138 ( Appt )>> Fax : 82-54-279-8137 (or +82-54-279-3399)>> Web :
>> http://csm.postech.ac.kr/ and http://www.postech.ac.kr/e>> Home Page :
>> http://www.geocities.com/njs_19>> --> Ilyas
>> ildirim> --------------------------------------------------------------->
>> - Department of Chemisty - -> - University of
>> Rochester - -> - Hutchison Hall, # B10 - -> - Rochester, NY
>> 14627-0216 - Ph.:(585) 275 67 66 (Office) -> -
>> http://www.pas.rochester.edu/~yildirim/ -> ------------------------------------
> -!
>> -------------------------->> ----------------------------------------------------------------------->
>> The AMBER Mail Reflector> To post, send mail to amber_at_scripps.edu> To
>> unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu>>>
>>
>
> I wrote a small script to calculate the free energy change of this
> simulation, and yes, it gave a deltaG = 0.15 (approx). But as I said, this
> result mean nothing. U have to do another simulation and subtract it with
> this one.
>
> If the only change is -CH3 --> -H, maybe it is reasonable. The
> experimental free energy of hydration of methane is 2.0 kcal/mol while it
> is 1.8 kcal/mol for ethane. The difference is 0.2 kcal/mol. (JACKS
> 1996, 118, 6285-6294; original data from Cabani et al. 1981) So, maybe the
> same thing is true for your system. Just a thought.
>
> Good luck,
>
>>
>>
>>
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>>
>
> --
> Ilyas Yildirim
> ---------------------------------------------------------------
> - Department of Chemisty - -
> - University of Rochester - -
> - Hutchison Hall, # B10 - -
> - Rochester, NY 14627-0216 - Ph.:(585) 275 67 66 (Office) -
> - http://www.pas.rochester.edu/~yildirim/ -
> ---------------------------------------------------------------
>
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