Subject: Summary: Dock4.0 + InsightII

From: "Jianhui Wu" <[email-masked]>
Date: Thu, 17 Feb 2000 10:46:11 -0500

Dear all,

A couple days ago, I asked a question about using InsightII to assign
ligand charges for Dock4.0. From the responses I got, people use
CVFF and Amber charges. Moreover, I was told that we can get charges
that is pretty similar to Gasteiger charges by using Cdiscover and ESFF
(just do the partial charge fix). I has been fortunate to have InsightII
to
play with although I do not have access to Sybyl.

Regarding the ``orientation tried = 0 `` question, it still puzzle me.
Probably,
the DOCK find the ligand is so different with the binding site, it
simply refuse
to waste CPU on it. This is my guess! If you know why, please share.

I would like to thank Thomas Huebner, Irene Nobeli and Elizabeth Yuriev
for
their help. Please find their responses as follow.

Regards,

Jian Hui Wu
[email-masked]

**************************************
Original Question:

Dear all,

(1). Assigning charges using insightII

I am using DOCK 4.0.1. Unfortunately, I have to use InsightII
instead of Sybyl to assign charges for ligands. My question is
what forcefield is more suitable for DOCK 4.0.1?

The receptor is assigned with Amber charge. However, it is
very difficult to assign Amber charge for a large database
(organic compounds) automatically. Therefore, I try to use
CVFF (consistent-valence forcefield). The docking result is
reasonable. However, I do not like the idea to mix two forcefield
in one calculation. (CVFF charge and Amber charge are derived
quite differently). At second thoughts, I might just go on doing it
as far as the result is good. But I am really not sure about it. Any
suggestion would be greatly appreciated.

By the way, regarding Gasteiger charges computed by Sybyl, is
there freeware that can produce similar charges at similar speed?

(2). Orientation tried   0, Orientation score 0, why?

Again, it is DOCK 4.0.1.  When I dock a single ligand,
I get a message that 0 orientation was tried and 0 orientation
was scored (in fact, it happens a dozens times to me now).
Yes, the ligand is small related to the binding site defined.
I thought this is the reason for that until I encounter an even
smaller molecule which DOCK processed it and scored it. How come
DOCK kick that first molecule out without even try one orientaion?
(The structure is correct. The min & max heavy atoms are correctly set).

Thanks a lot for your help.

Responses:
***********************************
(1)Thomas Huebner <[email-masked]>

>
>....
> reasonable. However, I do not like the idea to mix two forcefield
> in one calculation. (CVFF charge and Amber charge are derived
> quite differently).

What makes you think they are so different?
>>(PS:  It seems that Amber charges involve ESP, ab initio calculation.
>>CVFF is derived by fitting to crystal properties. Here, we are talking

>>about the old Amber charge. According to the MSI FAQs webpage,

>>http://www.msi.com/support/discover/forcefield/librarychg.html

>>it give me the above impression. However, I must admit that I did read

>>Amber forcefield paper and do NOT read the CVFF paper yet.  JH Wu)

>
> By the way, regarding Gasteiger charges computed by Sybyl, is
> there freeware that can produce similar charges at similar speed?

>From your remark on the misfortune of having to use Insight, I conclude
that you somehow might have access to Discover as well. If so, using
cdiscover (Discover_3 in the module list) and esff you will do the
"Partial_Charges Fix" with  method that is pretty similar to Gasteiger,
ie. smoothing out EN's.

************************************************************
(2)Irene Nobeli <[email-masked]>

I am by no stretch of the imagination an expert in DOCK, but I am
currently using DOCK4 and I have encountered some of your problems. Like

you, I have only InishgtII available to me, and hence, I cannot use the
suggested Gasteiger charges. However, I used cvff, and the results are
not
bad at all, so for all it is worth, this is my experience. Since AMBER
was
not developed for small molecules, and the DOCK manual suggests the use
of
AMBER charges, it seems that mixing of the forcefields is inevitable.
What
I had found more worrying was that InsightII assigns the old AMBER
charges
which were supposed to be used in conjuction with a hydrogen bond term.
However, I did replace those charges with the ones from Cornell et al
(the
new AMBER forcefield) and the results did not change qualitatively.
Later
on I was told that Sybyl also assigns the old charges (although I am not

sure about this, as I did not check myself) and hence this problem is
not
specific to InsightII.

As for your second question it seems like the orient_ligand parameter
was
set to "no"...If this is not the case, then perhaps you can e-mail me
the
"dock.in" file where all parameters are set and I could have a look..no
promises though!!
  ......
*************************************************
(3)Elizabeth Yuriev <[email-masked]>

Hi Jianhui,

Jianhui Wu wrote:

> I am using DOCK 4.0.1. Unfortunately, I have to use InsightII
> instead of Sybyl to assign charges for ligands. My question is
> what forcefield is more suitable for DOCK 4.0.1?

According to DOCK manual and literature, charges on ligands should be
Gasteiger-Marsili and atom types should be Tripos/Sybyl. I am dealing
with peptide
ligands and so I am using AMBER charges. In a recent paper (Proteins,
1999, 36,
1-19) Kuntz et al talks about atomic charge effect on the docking
results and using
AMSOL charges.

> By the way, regarding Gasteiger charges computed by Sybyl, is
> there freeware that can produce similar charges at similar speed?

I looked around and found none. Please let me know if you are more
lucky.

> (2). Orientation tried   0, Orientation score 0, why?

I had similar problems, but with conformations. Sometimes, changing
clash_overlap
helped. Again, if you get a solution, please share.

sincerely,
Elizabeth
*****************************************************
E.O.F