AMBER Archive (2005)

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

From: Jiten (jiten_at_postech.ac.kr)
Date: Sat Jun 25 2005 - 11:13:44 CDT

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.

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?

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 -28!
 .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 so!
 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 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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