Subject: Summary dendrimer modelling responses

From: "E.E.Moret" <[email-masked]>
Date: Tue, 20 Dec 94 22:47:06 MET

Dear colleagues,

Here is the summary of responses to my question on growing dendrimers
in computro. There seem to be several possibilities. Polygraf was mentioned
twice. CavityStuffer seems very promising when you consider the expected
boom of nanotechnology.
Thanks to all responders for their generous help.

With best regards and season's greetings,
Ed Moret

Date: Thu, 8 Dec 1994 07:10:04 -0600
From: [email-masked] (Toni Kazic)
Subject: Re: CCL:Dendrimer modelling

Klotho handles any number of branch points as a matter of routine.  We have not described
any dendrimers of the type you describe, but would be happy to.  We have not yet released
the code (we will, we just need to finishing writing it up), but would be happy to supply
pdb files within the limits of what can be generated by CONCORD.  We can of course provide
the equivalent of an enriched connection table.

Toni Kazic
Institute for Biomedical Computing
Washington University

Date: Thu, 8 Dec 1994 09:00:22 -0800 (PST)
From: [email-masked] (Walter E. Reiher III)
Subject: Re: CCL:Dendrimer modelling

E.E.Moret wrote:
> Dendrimers are branched polymers, resembling trees and branches, of an 
> organic repeat unit. Several theories on their potential use have been
> proposed (for example Jansen et al., Science 18 november 1994, 1226-1229). 
...
> We would appreciate any suggestions on research performed in this area and
> on programs that can cope with this special kind of "molecular growth".
> Replies, if any, will be summarised for CCL.

I am certainly not current in this area, but learned a bit about it a
few years back when I worked for a software company called BioDesign.
That company's polymer product, Polygraf, was capable of building,
displaying, and simulating dendrimers.  It was used in Bill Goddard's
research group at Caltech in some publications.  I know one graduate
student of Bill's who published in this area:  Adel Naylor; there are
probably others.  You might wish to check their publications near the
1989-1990 timeframe.
     BioDesign has since become a part of Molecular Simulations.  I'd be
very surprised if that Polygraf functionality wasn't somewhere in their
current product offerings.

Hope this helps!

Wally
========================================================================
Walter E. Reiher III, Ph.D.                            [email-masked]
Consultant in Computational Chemistry
P.O. Box 61056                                        voice 408-720-0240
Sunnyvale, CA 94088                                     fax 408-720-0378

Date: Thu, 8 Dec 94 11:23:06 -0300
From: [email-masked] (Augusto C. C. Neto)
Subject: First Contact

			Federal University of Sao Carlos, december 7, 1994

Dear Dr Moret

We are a experimental&theorical group developing ceramic and semiconductors
materials in Brazil . Nowadays I am working with Starburst dendrimers too, 
I'm using Hyperchem for SGI and Windows, MOPAC 5.0 and Gaussian to calculate
my molecules.

We are working with Carbon, Nitrogen and Benzene dendrimers. About constructing
the generations, they are handmade.

What kind of dendrimers's properties you would like to analise  ? Do you have
a good computer hardware ?

Sincerely 

						Augusto Cesar

Date: 08 Dec 1994 14:38:34 -0800 (PST)
From: [email-masked]
Subject: Dendrimers

Two quick points.

1) There a class of materials called aerogels that are made of
dendrimers.  For example resorcinal and formaldehyde link together with
three links to each phenyl ring.

2) I use to have POLYGRAF from Molecular Simulations and it had a
dendrimer growing option.  The problem in that you started with one
seed and grew generations out from it - if you wanted "loops" you
had to edit them in by hand.  What it created was like a Bethe lattice - 
and as such sooner or later you got molecular overlap.  I used it ot
make a few viewgraphs.

Dan Calef
[email-masked]

Date: date\r\e%, 8 Dec 1994 19:05:19 -0800
From: [email-masked] (kr)
Subject: Re: CCL:Dendrimer modelling

At 03:12 94-12-08, E.E.Moret wrote:
>We would like to study the influence of the conformation of
>the repeat-unit on the multiple-generation dendrimer that can be constructed.
>We are aware of software tools to polymerise repeat-units, especially
>the modules implemented in the commercial modelling packages. These
>modules, however, require ONE head and ONE tail atom to initiate
>polymerisation.
>Dendrimers, by definition, grow on 3 or more sites of the repeat unit.
>
>We would appreciate any suggestions on research performed in this area and
>on programs that can cope with this special kind of "molecular growth".

Dear Ed Moret

Until about one year ago, I have worked on a program that would likely be
able to accomplish what you are interested in (since then I essentially had
no time to further pursue this project). As the "official" description
attached below shows, the program I developed is called "CavityStuffer" and
was developed to study the design of folding polymers, which can be
tree-like with arbitrary branching patterns, and so starburst dendrimers
would be a subclass of the tractable structures. The goal of the program
was to construct polymers which are able to densely fill a prescribed
volume, to design protein-like building blocks that could be used for
self-assembly into larger structures.

The full goal has so far not been achieved, and I would have to invest more
work. The problem is that the current primitive (random) strategy is not
able to adequately fill the empty spaces (or it would take too much time to
be really useful). But there is a working framework of code that is able to
construct libraries of moieties (molecules that can be added as monomers)
and of links (which describe the attachment geometry between moieties).
Facilities for I/O using the PDB format exist, and a clash detector is able
to determine steric clashes in 3D space. There are facilities to manage the
tree-like polymer structures with additional associated infrastructure.
This framework could easily be extended to grow polymers of predefined
sequence (thereby not using certain sections of the program, which are
supposed to figure out suitable sequences by themselves :-).

The program is written in Common LISP, because it is a suitable language
for dealing with complex, arbitrary, and dynamically changing structures,
without the hassles of coding all the memory management stuff by hand. And
so it is practical for exploratory research. Of the useful and higher level
programming languages, Common LISP also has the advantage that it can be
obtained for running it on a wide variety of platforms. There are at least
two implementations available in source code that run on UN!X boxes, namely
GCL/AKCL and CLISP (the latter one from Germany).

I would be willing and interested to cooperate and help in adapting the
program to the use for starburst dendrimers and other purposes. The only
caveats are the following: some sections of the program are not yet very
user-friendly, and could use work on designing better facilities for
interaction, to which I did not yet get around to implement. Also, there is
little documentation, and I plan to write some both on the overall program
structure, as well as documenting individual subroutines. Possibly in a few
months from now, this better documentation will exist, and I will then post
the program on a ftp site for public downloading and experimentation. Until
that time, I would be willing to give a copy of the source code to
seriously interested parties, and help them as far as I can find time. The
only other caveat is that I am opposed to patents, and especially software
patents (contact <[email-masked]> for more info), and so I would object
if any part of the program used in derivative work would become covered by
patents. Note that even academic institutions often have aggressive
so-called technology transfer programs, which achieve exactly the opposite
by oppressing everybody's freedom. If it can be assured that CavityStuffer
can be held outside of these greedy hands, I encourage free use and
exploration.

The following is a description of the CavityStuffer program. Note that it
chooses the moieties (monomers) that ought to be attached using a random
strategy currently, but obviously this could be easily replaced by a
dictated, pre-defined sequence.

===========================================================================
CavityStuffer Program Description

Context

The anticipated development of molecular manufacturing capabilities and of
molecular nanotechnology hinges on being able to design and synthesize
molecular machinery, which consists of well-defined molecular aggregates of
a size which is fairly large by today's synthetic standards (linear dimensions
on the order of 100nm). Well thought-out ways of convergent synthesis and
convergent self-assembly have to be applied to achieve this goal.
The critical ability needed seems to be a routine way of designing and
synthesizing polymeric macromolecules of about the size of a medium protein.
They can be thought of as cubes with a side length of about 3nm. These
sub-units need to have complementary surfaces, specifiable to atomic detail,
and their cores have to pack into a rigid and immobile structure so that the
surface patterns are upheld in a stable fashion.

Description of the Program

The purpose of the CavityStuffer program is to propose tree-like polymeric
molecules, which when synthesized and allowed to fold into their globular
structure, will densely fill a given volume, the surface of which was
prescribed
to atomic detail. The CavityStuffer currently generates its proposals by
growing polymers blindly, choosing in a randomized fashion sites on the
tree for further
attachment and elongation. Once a site has been chosen, a moiety (monomer) is
selected from a library of allowed moieties, similar in concept to allowed
moves in a game of chess. The moieties are stored in the library as rigid,
three-dimensional puzzle-pieces (as rotamers), so the CavityStuffer program
works by trying to fit three-dimensional geometric shapes into the given
volume.
Whenever a chosen moiety does not fit (i.e. if it clashes with other atoms
already in place), it is discarded, and a different moiety will be tried
instead. This scheme largely avoids expensive numerical tasks such as energy
calculations (which are commonly used for studies of folding polymers such as
proteins), because clash-detection is quick. Because the generation of
individual proposals is fast, a large number can be generated automatically
without human supervision and sorted according to how well they fill the
volume.
There are various places in the program where one could add in smarter and
higher-level strategies than the random selection mechanism used now.

Current Status

As of November 1993, the basic machinery of the CavityStuffer program is
working.
One can build tree-like molecules using moieties provided by a library. There
are also tools to help with constructing the moiety-library, and there are
facilities for input and output via PDB files. The program is written in
CommonLISP and consists of about 15 files with about 250 lines each.
With a simplistic demo-version of the moiety-library, the packing of the
polymer is not yet very good. More work has to go into a careful design of a
good moiety-library which contains a high enough diversity of rotamers. Better
strategies need to be added as well, such as a pre-partitioning of the total
volume into smaller chambers, so that the packing becomes a more local task.

Acknowledgement

CavityStuffer by M. Krummenacker, with valuable input from K. E. Drexler.
The work has been funded through the Institute for Molecular Manufacturing,
Palo Alto, CA.
People interested in staying up-to-date on the development of this program
are welcome to send e-mail to <[email-masked]> .
===========================================================================

To understand more of the background thinking that has led to the tackling
of the CavityStuffer project, please read my paper describing design rules
for organic molecules to be used as molecular building blocks (Chem. Design
Autom. News, Vol.9, Jan '94, p.1). If you have difficulties finding this, I
can send you a copy if you supply me with your snail-mail ( v_@_ ) address.
I will be in Switzerland for one month starting from Dec. 14, so it would
be best to contact me before then, if you are interested.

>Replies, if any, will be summarised for CCL.

I would be interested in seeing a summary. I also do not mind if my message
here shows up on the summary.

Many Greetings
==================================================================
Markus Krummenacker                       1797 Union Street
Director of Research                      San Francisco, CA 94123
Nanothinc, A California Corporation       Phone: (415) 202-9969
direct email: [email-masked]            FAX:   (415) 202-9975
general info: [email-masked]          URL: Coming this fall

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E.E. Moret	(@more@)			    [email-masked]
Computational Medicinal Chemistry/Department of Pharmaceutical Chemistry
Faculty of Pharmacy/Utrecht University/the Netherlands
Telephone	(31-30)536979/536958        Facsimile      (31-30)516674
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