Dear David
Thanks a lot for your detailed answer.
I will try your suggestion and report back.
Best regards,
Fabian
Fabian Glaser PhD
Head of the Structural Bioinformatics section
Bioinformatics Knowledge Unit - BKU
The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering
Technion - Israel Institute of Technology, Haifa, Israel
Web
http://bku.technion.ac.il/
Tel +972 (0) 4 8293701
> On 31 May 2019, at 4:20, David Case <david.case.rutgers.edu> wrote:
>
> On Wed, May 29, 2019, Fabian Glaser wrote:
>>
>> Here, there is a PTR (phospho tyrosine) bound to the DNA through a C5’
>> atom of DA. Tleap works, but the problem is that instead of making a bond
>> between C5’ and OP1, it treats the DA as a terminal DA5 and adds a O5’
>> (not present in the original pdb), which is wrong.
>
> This, along with many other covalent modifications, is hard to model in
> Amber. Here's what I would do, at least to start:
>
> 1. Load the PTR residue into xleap, and remove the hydrogen, and/or any
> other atoms you don't need. Save under a different name.
>
> 2. Load DA5 into xleap, remove the O5', save under a new name (say DA6).
>
> 3. Modify the PdbResMap commands in your leaprc file to have leap use
> DA6 as the 5' terminal adenosine rather than DA5.
>
> 4. Load your peptide/protein (with modified PTR) and DNA (with modified
> DA5) into tleap, and use the bond command to add the cross-link between
> PTR and DA6.
>
> 5. Modify by hand the charges in the PTR-DA6 region to be close to the
> originals yet sum to the proper value; create a frcmod file to handle
> any missing parameters.
>
> Obviously: be prepared for hurdles, and check carefully that the
> resulting prmtop file makes sense: parmed is a convenient way to examine
> what you have.
>
> I suggested the above approach because there is actually little
> modification to standard residues, and I'm assuming/hoping that the
> rotational profiles about the phosphate bond connecting DA and TYR are
> similar to those in DNA itself. You could also treate the PTR-DA unit
> as a novel residue, and start to parameterize that from scratch. But my
> approach tries to make as few changes from standard protein/DNA force
> fields as seems to make sense.
>
> [There are efforts in the Amber community, led by Chris Schafmeister, to
> completely revamp the way problems like this can be approached. But
> that's still in development. I'd be interested in hearing how CHARMM or
> GROMACS handles this sort of situation.]
>
> ...regards...dac
>
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Received on Sun Jun 02 2019 - 06:30:04 PDT
