Subject: Re: CCL: Hydrophobic ligands (was molecular docking startup)

From: Richard Gillilan <[email-masked]>
Date: Tue, 26 Feb 2002 09:23:04 -0500

Interesting. Anyone else have comments on docking hydrophobic ligands?

Right away I can think of a couple reasons why hydrophobics would be
difficult. Without strong, directed polar interactions, the binding
site would naturally be shallower and less well defined. Docking
programs without a good solvent model may also contribute to the
problem, but I wonder if that is really a significant factor or not.

There was a paper just out in J. Comp. Chem. about the failure of 
point charge models to correctly reproduce crystal lattices of n-alkanes:

"On the irrelevance of electrostatics for the crystal structures and 
 polymorphism of long even n-alkanes"
 Jacco Van de Streek, Paul Verwer, Piet Bennema, Elias Vlieg
 (JCP v23 #3 2002)

Anyone worked with the Thermal Motion Forcefield (TMFF) mentioned
in the article, or know where the paper is supposed to come out?

Richard Gillilan
MacCHESS

> Stewart Kirton wrote:
....
> recommend that you start here. However, it has limitations - and if you
> are looking to dock largely hydrophobic ligands into hydrophobic
> structures it probably will frustrate you......saying that so will a lot
> of the other packages out there.
>

---

From: Jacco van de Streek <[email-masked]>
Date: Tue, 26 Feb 2002 17:05:11 +0000

> in the article, or know where the paper is supposed to come out?

The paper has been accepted for publication in Acta Crystallographica section B,
the revised manuscript has just been sent to the referees again.

I would like to stress that TMFF was developed only as a means to show that
thermal motion explains the structural discrepancies between experimental and
statically minimised crystal structures for long even n-alkanes (till now, it
had either been published that thermal motion was irrelevant, or that
electrostatics might be paramount: both views will lead to wrong structures and
wrong relative energies) and that is the only thing we claim it can do (very
important if you do polymorph predictions and want to minimise approx. 10,000
crystal structures per conformation per compound and compare each to an
unindexed experimental powder pattern, triclinic, one long unit cell axis, two
short). Relative energies between two polymorphs are also greatly improved, but
we don't know about absolute energies.

It would be nice if someone could validate the usefulness of TMFF outside this
rather narrow area of application. Implementing TMFF in GOLD is technically
feasible (I just checked with one of the programmers: by pure chance, GOLD
happens to be partially developed here at the Cambridge Crystallographic Data
Centre where I work now, the work on TMFF was done at the University of
Nijmegen). Note though, that TMFF has only been parameterised for Carbon and
Hydrogen.

Jacco.
-- 
Jacco van de Streek
Research Scientist
Cambridge Crystallographic Data Centre
Cambridge
United Kingdom