Subject: Re: CCL:Molecular Mechanics

From: [email-masked] (Eberhard von Kitzing)
Date: Wed, 22 Nov 1995 08:38:37 +0100 (MET)

Dear Paddy Kane,

>  The reason that I ask is that I obtained the following energies from 
> MM optimizations for complexes of the same ligand but with different 
> ions:
> 		Energy/ (kcal / mol)
> Li+		-190.6
> Na+		-171.2
> K+		-150.8
> 
>  We have found experimentally that the ligand is selective for 
> sodium over magnesium; so I would have expected to have obtained a 
> lower energy for the sodium complex. So *IF* MM optimization 
> energies are not a reliable indicator of selectively what exactly is 
> the significance of the above difference of 63 kcal / mol?

I think this energy has some relevance. But in comparing the results 
you have to consider that in experiment you take the ions out of 
water and not out of vacuum. You have to include hydration energies. 
You have to look first which energies may be important in your 
experimental binding studies and than have to think about how to 
estimate them using MM etc.  

There are several levels you could use. The simplest one would be to
use experimental hydration energies. The next level would be to
estimate the hydration energy using the same force field. Possibly,
the ligand also requires some hydration because a water molecule may
be replaced by the ion.

The most sophisticated, but not necessarily the most reliable, method
would be to put the ligand in water and evaluate the free energy
difference by mutating the water molecule closest to the binding site
into an ion. This method requires very careful evaluations and will
certainly take much time. 

-------------------------------------------------------------------------

Eberhard von Kitzing
Abteilung Zellphysiologie
Max-Planck-Institut fuer Medizinische Forschung
Jahnstr. 29, D69120 Heidelberg, FRG

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