AMBER Archive (2005)

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

From: Ilyas Yildirim (yildirim_at_pas.rochester.edu)
Date: Mon Jun 27 2005 - 18:43:16 CDT

Hi Jiten,

I just checked out the ALA and GLY residues. GLY residue has two H1 type
hydrogen attached to CT type of carbon. So, I would do a CT->H1
transformation, rather CT->H0 transformation. Generally, a CT type carbon
has H1 type hydrogens, but in ALA residue, it has HC type hydrogen. Thats
interesting. But in any case, I would do CT->H1.

Good luck.

On Tue, 28 Jun 2005, Jiten wrote:

> Hi Ilyas Yildirim,
>
> In the system setup in solvent (second step of TI) for the TI method using
> xleap for A-->G, I have something like the attached file.
>
> My concern is CT --> HO : is it the right choice?
>
> Thanks for your help.
>
> 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/ -> ------------------------------------
> > -!
> >> -------------------------->> ----------------------------------------------------------------------->
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> >>
> >
> > 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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> >
> >
> 

-- 
  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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