AMBER Archive (2005)

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

From: Ilyas Yildirim (yildirim_at_pas.rochester.edu)
Date: Tue Jun 28 2005 - 00:46:17 CDT

Hey Jiten,

Which version of AMBER are u using? According to AMBER 8, the definition
is given in the AMBER manual page # 34. U can download the .pdf version of
AMBER 8 from the following address:

http://amber.scripps.edu/doc8/amber8.pdf

According to AMBER 8, pert.charge is the difference between the perturbed
charge and the regular charge. But as I said, this is according to AMBER
8. Probably it is different in AMBER 7. Just check this manual out.

As for the atom type, I loaded leaprc.ff99 force field parameters, and
checked out the ALA and GLY residues. In this FF, GLY's carbon atom (CT)
had two hydrogens with H1 atom type. I didnt check out how it is in the
other force fields. I am sure the FF03 is the best force field for the
proteins.

Good luck,

On Tue, 28 Jun 2005, Jiten wrote:

> Hai Ilyas Yildirim and amber users,
>
> As I am using the FF03 with amber8 (with all_amino03.in, however I use xleap
> of amber7 for making my input files) GLY has two H0 type attached to CT.
> Therefore it would be fine with H0 atome type.
>
> However, what is more concerning to me is on your comment
>
> > I just realized something in your attached file: Your charges looks wrong.
> > For instance, when u do the HC->DH transformation, the dummy atoms will
> > have a zero charge in them. That means that the PERT.charge should be
> > -0.0774 (according to AMBER 8). Which version of AMBER are u using? In
> > Amber 8, the pert.charge is delta(charge), which is (charge of the state 1
> > atom - charge of the state 0 atom). So, at state 1, u will have a dummy
> > atom which has a zero charge in it. As a result (0 - 0.0774) = -0.0774
> > should be in the PERT.charge column for this particular HC->DH
> > transformation. You should do the same thing for the other atoms. If their
> > final charge is different than the initial state charges, u should
> > subtract them, and put that value into the PERT.charge column.
>
> I am bit confused at this part. I have replaced the charges of ALA by GLY,
> thereby the Dummy atom charges are set to zero. Therfore total pert.charge
> of the system is also zero. Am I still doing wrong ?
>
> Any suggestions will be highly appreciated.
>
> Sincerely,
>
> Jiten
>
> ----- Original Message -----
> From: "Ilyas Yildirim" <yildirim_at_pas.rochester.edu>
> To: <amber_at_scripps.edu>
> Cc: "Jiten" <jiten_at_postech.ac.kr>
> Sent: Tuesday, June 28, 2005 8:43 AM
> Subject: Re: AMBER: TI-FEP for VAL --> ALA
>
>
> > 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
> >> >>
> >> >> ldirim> --------------------------------------------------------------->
> >> >> - Department of Chemisty - -> - University of
> >> >> Rochester - -> - Hutchison Hall, # B10 - -> - Rochester,
> >> >> NY
> >> >> 14627-0216 - Ph.:(585) 275 67 66 (Office) -> -
> >> >>
> >> >> ttp://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,
> >> >
> >> >>
> >> >>
> >> >>
> >> >> -----------------------------------------------------------------------
> >> >> The AMBER Mail Reflector
> >> >> To post, send mail to amber_at_scripps.edu
> >> >> To unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu
> >> >>
> >> >>
> >> >
> >> > --
> >> > 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/ -
> >> > ---------------------------------------------------------------
> >> >
> >> > -----------------------------------------------------------------------
> >> > The AMBER Mail Reflector
> >> > To post, send mail to amber_at_scripps.edu
> >> > To unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu
> >> >
> >> >
> >> >
> >>
> >
> > --
> > 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/ -
> > ---------------------------------------------------------------
> >
> >
> > -----------------------------------------------------------------------
> > The AMBER Mail Reflector
> > To post, send mail to amber_at_scripps.edu
> > To unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu
> >
> >
> >
> 

-- 
  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/			-
  ---------------------------------------------------------------

-----------------------------------------------------------------------
The AMBER Mail Reflector
To post, send mail to amber_at_scripps.edu
To unsubscribe, send "unsubscribe amber" to majordomo_at_scripps.edu