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Hi,<br><br>
I've recently been computing free energies of hydration by
converting<br>
all-atoms in a molecule to non-interacting dummy atoms in water and
<br>
vacuo. DeltaG hydration then equals the difference between this
free-energy<br>
change in vacuo and this free-energy change in water. I have been
getting good<br>
results (in comparison with experiment) for my hydration free
energy<br>
calculations using dummy atoms which I define in my .top file.<br><br>
However, I've been trying to set up some alchemical simulations lately
and these<br>
aren't working as well. As you can see in the attached topology file,
I'm<br>
morphing ethane into ethane, which should (obviously) have a net free
energy<br>
change of zero. I'm trying to mimic a study published by David
Pearlman ("A<br>
Comparison of Alternative Approaches to Free Energy Calculations" J.
Phys.<br>
Chem. 1994, 1487-1493). I start with a propane molecule and use
pdb2gmx<br>
to get a .top file. Then I change some atoms to be dummies such
that at lambda <br>
= 0 and 1, only ethane is present additional dummy atoms attached.
The dummy<br>
groups switch from one side of the molecule to the other over the course
of the<br>
simulation.<br><br>
I've been using windows of lambda to estimate dG/dlambda for lambda
between 0<br>
and 1, but unfortunately, my results for dG/dlambda are only roughly, and
not<br>
exactly, symmetric. Also the results are very noisy, even for
simulation times<br>
MUCH longer than reported by Pearlman in his paper (a factor of 1000
longer). <br>
Instead of getting a free energy change of zero I get results between -30
and<br>
30 kJ/mol (depending on implementation details and simulation
time). I get similar<br>
problems in vacuo and water, although transformations in both
environments should<br>
have a deltaG of zero.<br><br>
Is the way I am implementing dummy atoms with OPLS correct? Because
I was<br>
getting OK results for my hydration free energy calculations I thought it
would<br>
be, but maybe there is something I'm doing incorrectly for alchemical
changes?<br><br>
Is there something else I am missing?<br><br>
Thanks very much for your help,<br>
Brian <br><br>
<br>
<pre>;
;<x-tab> </x-tab>File
'ethane_al.top' was generated
;<x-tab> </x-tab>By user:
bstephenson (503)
;<x-tab> </x-tab>At date: Sun
Jul 10 16:46:37 2005
;
;<x-tab> </x-tab>This is your
topology file
;<x-tab> </x-tab>"Shake
Yourself" (YES)
;
; Include forcefield parameters
#include "ffoplsaa.itp"
[ atomtypes ]
;type
mass<x-tab> </x-tab>
charge ptype
c6
c12
DUMH<x-tab> </x-tab>1.008<x-tab> </x-tab>
0.0000 A
0.0 0.0
[ bondtypes ]
HC
DUMH<x-tab> </x-tab>1<x-tab> </x-tab>0.070<x-tab> </x-tab>284512.0
; H to dummy H using CT to H bond distance and potential
[ angletypes ]
DUMH HC<x-tab> </x-tab>
DUMH 1
107.800 276.144 ; CHARMM 22 parameter file
for HC CT HC used for dumh h dumh interaction
CT<x-tab> </x-tab>
HC<x-tab> </x-tab>
DUMH 1
110.700 313.800 ; CHARMM 22 parameter file
for CT CT HC used for c h dumh interaction
[ dihedraltypes ]
DUMH
HC<x-tab> </x-tab>CT<x-tab> </x-tab>HC<x-tab> </x-tab>3
0.00000 0.00000 0.00000
0.000000 0.00000 0.00000 ; hydrocarbon *new*
11/99
CT<x-tab> </x-tab>CT<x-tab> </x-tab>HC<x-tab> </x-tab>DUMH
3 0.00000 0.00000
0.00000 0.000000 0.00000 0.00000 ;
hydrocarbon all-atom
<x-tab> </x-tab>
[ moleculetype ]
; Name
nrexcl
ETH
3
[ atoms ]
; nr type resnr
residue atom cgnr
charge mass
typeB chargeB massB
1
opls_135 1
ETH CH1
1 -0.18
12.011
opls_140<x-tab> </x-tab>0.06<x-tab> </x-tab>1.008;
qtot -0.18
2
opls_140 1
ETH OH11
1 0.06
1.008
DUMH<x-tab> </x-tab>0.0<x-tab> </x-tab>1.008;
qtot -0.12
3
opls_140 1
ETH OH12
1 0.06
1.008
DUMH<x-tab> </x-tab>0.0<x-tab> </x-tab>1.008;
qtot -0.06
4
opls_140 1
ETH OH13
1 0.06
1.008
DUMH<x-tab> </x-tab>0.0<x-tab> </x-tab>1.008;
qtot 0
5
opls_135 1
ETH CAA
1 -0.18
12.011 ; qtot -0.18
6
opls_140 1
ETH HAA1
1 0.06
1.008 ; qtot -0.12
7
opls_140 1
ETH HAA2
1 0.06
1.008 ; qtot -0.06
8
opls_140 1
ETH CH2
1 0.06
1.008 opls_135 -0.18 12.011; qtot 0
9
DUMH
1 ETH OH21
1
0 1.008
opls_140<x-tab> </x-tab>0.06<x-tab> </x-tab>1.008;
qtot 0
10
DUMH
1 ETH OH22
1
0 1.008
opls_140<x-tab> </x-tab>0.06<x-tab> </x-tab>1.008;
qtot 0
11
DUMH
1 ETH OH23
1
0 1.008
opls_140<x-tab> </x-tab>0.06<x-tab> </x-tab>1.008;
qtot 0
[ bonds ]
; ai aj
funct
c0
c1
c2 c3
1 2 1
1 3 1
1 4 1
1 5 1
5 6 1
5 7 1
5 8 1
8 9 1
8 10 1
8 11 1
[ pairs ]
; ai aj
funct
c0
c1
c2 c3
1 9 1
1 10 1
1 11 1
2 6 1
2 7 1
2 8 1
3 6 1
3 7 1
3 8 1
4 6 1
4 7 1
4 8 1
6 9 1
6 10 1
6 11 1
7 9 1
7 10 1
7 11 1
[ angles ]
; ai aj ak
funct
c0
c1
c2 c3
2 1
3 1
2 1
4 1
2 1
5 1
3 1
4 1
3 1
5 1
4 1
5 1
1 5
6 1
1 5
7 1
1 5
8 1
6 5
7 1
6 5
8 1
7 5
8 1
5 8
9 1
5 8
10 1
5 8
11 1
9 8
10 1
9 8
11 1
10 8
11 1
[ dihedrals ]
; ai aj ak al
funct
c0
c1
c2
c3
c4 c5
2 1
5 6 3
2 1
5 7 3
2 1
5 8 3
3 1
5 6 3
3 1
5 7 3
3 1
5 8 3
4 1
5 6 3
4 1
5 7 3
4 1
5 8 3
1 5
8 9 3
1 5
8 10 3
1 5
8 11 3
6 5
8 9 3
6 5
8 10 3
6 5
8 11 3
7 5
8 9 3
7 5
8 10 3
7 5
8 11 3
; Include Position restraint file
#ifdef POSRES
#include "posre.itp"
#endif
; Include water topology
#include "spc.itp"
#ifdef POSRES_WATER
; Position restraint for each water oxygen
[ position_restraints ]
; i funct
fcx
fcy fcz
1 1
1000
1000 1000
#endif
; Include generic topology for ions
#include "ions.itp"
[ system ]
; Name
ETH
[ molecules ]
; Compound #mols
ETH
1
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