[gmx-users] Thermodynamic Integration Glu -> Ala Mutation

[Sai Kumar Ramadugu]

Dear Gromacs Users,
I am trying to find out the relative free energy difference of binding of a
ligand with wild type protein (Glutamate residue) and mutant protein
(Alanine residue).

For charge part of the mutation, this is what I'm planning to do:

; residue  40 GLU rtp GLU  q -1.0
   552   opls_238      40    GLU      N      191       -0.5    14.0067
 opls_238    -0.5      14.0067 ; qtot 0.5
   553   opls_241      40    GLU      H      191        0.3      1.008
   opls_241     0.3     1.008 ; qtot 0.8
   554  opls_224B     40    GLU     CA    191       0.14     12.011
 opls_224B    0.14   12.011 ; qtot 0.94
   555   opls_140      40    GLU     HA    191       0.06      1.008
opls_140     0.06    1.008 ; qtot 1
   556   opls_136      40    GLU     CB    192      -0.12     12.011
 opls_135     -0.18   12.011 ; qtot 0.88
   557   opls_140      40    GLU    HB1    192       0.06      1.008
 opls_140      0.06    1.008 ; qtot 0.94
   558   opls_140      40    GLU    HB2    192       0.06      1.008
opls_140      0.06    1.008 ; qtot 1
   559   opls_274      40    GLU     CG    193      -0.22     12.011
opls_140     0.06    1.008 ; qtot 0.78
   560   opls_140      40    GLU    HG1    193       0.06      1.008
DUM_140    0.0      1.008 ; qtot 0.84
   561   opls_140      40    GLU    HG2    193       0.06      1.008
DUM_140    0.0      1.008 ; qtot 0.9
   562   opls_271      40    GLU     CD     194        0.7     12.011
DUM_271    0.0     12.011 ; qtot 1.6
   563   opls_272      40    GLU    OE1    194       -0.8    15.9994
DUM_272   0.0     15.9994 ; qtot 0.8
   564   opls_272      40    GLU    OE2    194       -0.8    15.9994
 DUM_272    0.0     15.9994 ; qtot 0
   565   opls_235      40    GLU      C      195        0.5     12.011
opls_235     0.5     12.011 ; qtot 0.5
   566   opls_236      40    GLU      O      195       -0.5    15.9994
 opls_236    -0.5    15.9994 ; qtot 0


I added the DUM_140, DUM_271,DUM_272 atomtypes in ffnonbonded.itp.
Further I added the bondtypes, angletypes and dihedraltypes in ffbonded.itp
for state B.

In order to maintain the electroneutrality, I am mutating a K+ ion to dummy
as well. For the K+ going to dummy, I added a DUM_408 atomtype as well.

*The questions I have are as follows:*
*During the charge mutation will my dummy atoms have sigma and epsilon as
0.0? Since Ala residue does not have Cgamma, Cdelta and the oxygen as well
as the Hgamma, all the dummy atoms should have sigma and epsilon as zero.
Am I correct for this assumption?*
*Further as I am mutating one ion, I dont want the mutating ion to come
close to other ions (I have three K+ ions as my protein has -3 charge) as
well as the protein atoms. Hence I'm having position restraints on the
three ions. *
*For the ion that is mutating to dummy, should I have have position
restraints on dummy atom as well for the B state topology?*

The section of topology for the K+ going to dummy is as follows:

[ moleculetype ]
; Name            nrexcl
KM               1

[ atoms ]
;   nr       type  resnr residue  atom   cgnr     charge       mass  typeB
   chargeB      massB
 1  opls-408      1       KM        KM        1      1        39.0983
DUM_408   0.0         39.0983

#ifdef POSRES_ION
; Position restraint for each Potassium ion
[ position_restraints ]
;  i funct       fcx        fcy        fcz
   1    1       1000       1000       1000   0       0       0
#endif

Here I defined the KM as K+ that will go to dummy and other two K+ ions are
represented as regular K+ ions.
I'm pasting the regular K+ ion part of the topology below.

[ moleculetype ]
; Name            nrexcl
K               1

[ atoms ]
;   nr       type  resnr residue  atom   cgnr     charge       mass  typeB
   chargeB      massB
 1  opls_408      1       K       K        1      1        39.0983

#ifdef POSRES_ION
; Position restraint for each Potassium ion
[ position_restraints ]
;  i funct       fcx        fcy        fcz
   1    1       1000       1000       1000
#endif

Let me know if you need more information.

Thanks for your time,

Regards
Sai
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