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

[Sai Kumar Ramadugu]

Any suggestions on this topic?
Thanks again for your time.


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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