AMBER Archive (2007)

Subject: Re: AMBER: antechamber fails with large molecules

From: FyD (fyd_at_q4md-forcefieldtools.org)
Date: Sun Nov 04 2007 - 06:29:09 CST

Quoting Francesco Pietra <chiendarret_at_yahoo.com>:

> What you are saying (and other subscribers said in parallel
> interventions) does
> not apply to organic chemistry/natural product chemistry, except perhaps in
> rare out-of-the-norm cases, if any.

This is difficult to answer without knowing your molecule. But, I do
not see very well in what this would not work in your case...

You can always split a molecules into two parts; the difficult part is
to find the correct way to do it ;-) Many examples are available in
the literature. The first description of this type of work is in
_Cieplak et al. J. Comput. Chem., 1995, 16, 1357-1377_. By analogy,
you can imagine many other strategies...

> At any event, I am not aware of any single
> example of treating a complicated organic molecule as residues to be
> recomposed later.

We are going to release a bunch of force fields in R.E.DD.B. Just need
a little time to make them available... You will find different
examples of fragment building for nucleic acids and derivatives,
sugars, organic molecules, complexes.

> The reason is simple: any portion is generally highly flexible - which
> defeats any choice of residues - and any portion you can conceive interacts
> strongly with neighboring portions.

???

Sugars are flexible & the Glycam force fields (for instance) are based
on fragments. So flexibility is not a reason.

Moreover, if your molecule is flexible, a strategy based on fragments
should be an advantage as you can rigorously study the flexibility (I
mean by QM) of each molecule part taken individually.

> No repetitive units,

OK a point for you ;-)

> very scarce similarity
> with units in other families of compounds, and a behavior that
> depends on large sections of the molecule, if not, in many cases, on
> the whole.

OK, Let's take two examples:

1) Do you have a peptide bond in your molecule ?
If yes, you can split your system as follows:

Big molecule:
R1-NHCO-R2 => R1-NH-ACE + NME-CO-R2
                     <-> <->
2 Intra-molecular charge constraints set to zero for ACE & NME.
See a similar approach @
http://q4md-forcefieldtools.org/Tutorial/Tutorial-1.php#10 ; See
Scheme 1

2) Do you have an ether/acetal/hemiacetal linkage ?
If yes, you can split your system as follows:

Big molecule: R1-O-R2
=> R1-O-Me + HO-R2
         <----->
1 Inter-molecular charge constraints set to zero for Me (molecule 1) &
HO (molecule 2)
See a similar approach @
http://q4md-forcefieldtools.org/Tutorial/Tutorial-1.php#11 ; See
Schemes 2 & 3

The F-71 project availble in R.E.DD.B. is an example of such an approach:
F-71 Multi-mannosides based on carbohydrate scaffold
However, this project is protected for a full year. The paper is
published: I can send the description of the force field topology
database building if you wish... A jpg image is available in the
project to describe the building strategy.

Gouin et al. Multi-mannosides based on carbohydrate scaffold:
synthesis, force field development, molecular dynamics studies and
binding affinities for the lectin ConA, J. Org. Chem., 2007, in press.

3) You can imagine your own splitting procedure. We are going to
release different others in R.E.DD.B. based on R.E.D. IV.

I hope this helps, regards, Francois

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