Subject: Charge model for simulating protein ligand complex

From: Guosheng Wu <wu_guosheng2002(at)yahoo.com>
Date: Thu, 2 Dec 2004 18:20:58 -0800 (PST)

Hello everyone,

I guess there seems no consensus so far on what's the best charge model
for molecular mechanics.  

Still one would like to use a consistent and decent (hopefully) model, but
the problem I am seeing is that many times people are used to applying
different charge models for the simulation of a protein ligand complex. 
At least I see many papers with such kind of approach.

Typically, a quick method such as Gasteiger charge is used for the ligand
(small molecule), but more "accurate" charge model (such as CHARMM,
AMBER...) is used for protein atoms.  However, I am very surprised to see
the atomic charges could be very different between Gasteiger model and
Quanta templates(CHARMM like charges?), for either protein or ligand. 

One example shown below is for 1gih (one kinase complex) generated from
Quanta program. The signs can even be different:

Atom_ID	type  Gasteiger	Quanta_template	  Quanta_template - Gasteiger
532	HZ2	-0.09	0.35	                  0.44
520	NZ	0.38	-0.30	                 -0.68
L_4	C7	0.25	0.59	                  0.34
L_13	O13	-0.27	-0.56	                 -0.29
1253	H	0.15	0.25	                  0.10
1245	N	-0.30	-0.40	                 -0.10
1246	CA	0.10	0.05	                 -0.05
1247	C	0.23	0.60	                  0.37
1248	O	-0.27	-0.55	                 -0.28
L_16	N16	-0.25	-0.41	                 -0.16
L_35	H12	0.06	0.12	                  0.06
L_15	C15	0.31	0.59	                  0.28
L_17	O17	-0.25	-0.56	                 -0.31
[Atom ID for protein or ligand(L_*) ]

So it seems true that the results based on such kind of charging approach
(protein from an "accurate" model like CHARMM, ligand from quick model
like Gasteiger) could be very unrelible.  

Does anyone have better ideas on this issue?   Should we start to blame
more on the charge models when we can not get good results?  Maybe the
best choice is to stick to a single model, (Is Gasteiger charge OK for
protein ?), at least the error might be systematically adjusted. 

-Guosheng 

__________________________________________________
Do You Yahoo!?
Tired of spam?  Yahoo! Mail has the best spam protection around 
http://mail.yahoo.com