[gmx-users] Re: Some additions to the free energy question

Markus O Kaukonen mokaukon at cc.helsinki.fi
Wed Sep 8 09:17:13 CEST 2004

Dear All,

Is it really a good idea to calculate free energy
differences of the two 'inhibitors' docking from
vacuum to protein (see the original question below, manual fig 3.9b)
when these two inhibitors differ each other by 'only' one proton by
'mdrun -rerun' method, that is calculating energies of one trajectory
using the topology of the other one.

In the case when the difference of I and I' is one proton it is not
just the proton but many structural rearrangements of aminoacids
(in E and I/I') and re-arrangement of the water network (in E).
The energy gain in the rearrangement can easily be 100kJ/mol.

So does one still think that the 'mdrun -rerun' is a good idea here
or should one consider the "slow growth" method described in the
manual in sec 3.12. Or is the difference between IE and I'E
too big in this case and neither of methods does work?

The examples in FAQ
1) a diffenrent charge distribution
   (J. Phys. Chem. B 106, 8858-8869, 2002)
2) changing ligand from one group 1 element to another (Li to K or Na)
seem to be much milder disturbances to I.

I'd also be gratefull for references concerning "slow growth"
method described in sec. 3.12 (a review type with lots of comparisons
between theory and experiment, as usual)...

Terveisin, markus.kaukonen at iki.fi

>Is it possible (cpu and otherwise) to do a free energy calculation for a
>system like in the manual (v 3.2 manual) page 36, fig. 3.9 case B
>ie. two different inhibitors (I and I') docking the same enzyme (E)
>when I and I' differ by one H+ (and the partial charges in I and I' are

>I (one system) and I' (the other system) have about 200 atoms and
>E has 70000 atoms.

>It seems at least that one has to do lot of things by hand in the
>file (for things related to those 200 atoms).

>Terveisin, markus.kaukonen at iki.fi

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