AMBER Archive (2008)

Subject: Re: AMBER: seeking help regrading Zinc protein GBSA minimization

From: Carlos Simmerling (
Date: Mon Dec 01 2008 - 05:16:02 CST

it means to do what I said- check the radii and see what is being
used. check the archives. they they aren't correct, then the energies
are not correct.
perhaps there is a different problem, it was just a suggestion.
good luck

On Mon, Dec 1, 2008 at 3:14 AM, Sergey Samsonov
<> wrote:
> Hi,
> could this mean that by default the components of MM energies in the systems
> with Zn2+ are not relevant to estimate and compare? Below I copy my question
> I had about the system with Zn2+ ion.
> Thank you very much in advance,
> Sergey
> ---------
> Hi AMBERs,
> recently we've been calculating MM-GBSA energy of binding of ligands
> (dipeptides) in the enzyme catalytic center, where Zn2+ coordination is
> carried out by ligand carboxyl group and, therefore, Zn2+ was considered as
> a part of the receptor. However, MM-GBSA results did not correlate with the
> experimental data, which we explained by the fact that 1. There is quite an
> important influence of water molecules (MD was done with explicit solvent
> and TIP3PBOX) building hydrogen bonding network with Zn2+ ion and mediating
> interactions between a ligand and the receptor 2. To many charges in
> comparably small the binding site. So in the next step we took explicitly
> water molecules (with the command closest) around the ligand and calculated
> simply MM energies. The results correlated nicely with the experimentally
> observed trends. As far as we used standard amino acids, this approach
> worked. However, when we tried to use methyl-carboxyl group at the
> N-terminus of the dipeptide, parametrized by the standard RESP procedures
> with the use of the already existing corresponding atom types from the force
> field (frcmod03, parm99.dat), the energies, obtained by MM, had really
> strange values. For example, it was obvious from the visual inspection of
> the MD simulation that the methyl-carboxyl group stabilized the interaction
> by VDW contacts and also the introduction of the group contributed favorably
> to electrostatic interactions (additional hydrogen bonds and salt bridges
> were formed). Nevertheless, electrostatic component of MM in binding energy
> was 200 kcal/mol less favorable than for not methyl-carboxylated variant of
> the ligand. The attempt to parametrize the whole amino-acid with the
> methyl-carboxylated group as a new residue led to the same results.
> Previously we had successful experience with RESP charge calculations and
> libraries creation for non-standard amino acid residues as well as their use
> for MM-PBSA/MM-GBSA calculations.
> Do you think we could do something principally wrong or the system could be
> under certain limitations for the method because of the comparably small
> size of ligand and quite a charged environment in the binding site?
> We would appreciate very much any suggestion.
> Sergey Samsonov
> ---------------------------------
> Carlos Simmerling wrote:
>> I would check to see what solvation radii are being used for the Zinc,
>> that's like the problem since it's only used in the GB calc and not
>> the explicit water one. look carefully in your leap and sander outputs
>> for messages related to this. you might also check to see if the GB
>> energy is going down a lot when this happens. I recall this being
>> discussed before on the list, so you should check the archives. search
>> for zinc radii or zinc radius.
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