Dear Yun,
> I looked at the CD project, and I saw when FFTopDB were constructed, the
> 1-metylated glucose was used to derive RESP charges. So in my
> thio-glycopeptide case, should I use the sugar molecule with a methyl group
> attached to the glycosidic sulfur as well?
>
> What about the modified (C-terminal reduced) amino acid? Add one more
> methyl group to the modified C-terminal and acetate to the N-terminal?
-1- Either you consider your Thio-L-Rhamno-Cysteine as a single residue:
-> in this case you prepare the corresponding dipeptide i. e.
ACE
Thio-L-Rhamno-Cysteine
NME
A young student in the lab has recently developed the automatic
generation of the Central, N-terminal and C-terminal fragments for a
modified amino-acid from a _single_ dipeptide in R.E.D. Server.
Please see: http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#25
versus
http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#24
This means here you only have to provide the correct conformation for
the phi, psi dihedrals for the peptide backbone and for the dihedrals
for the thio-glycosidic linkage in the PDB file and R.E.D. Server does
the job in two steps (i) generate the P2N file and (ii) does the
multi-building block job from the single dipeptide you provide.
-2- Or you decide to split your Thio-L-Rhamno-Cysteine into two residues
(more complex but far more flexible...)
ACE
L-Rhamno-S-Me + HS-Cysteine
<-------> NME
In this case you follow the tutorial .
http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#24 but you
need to add a seventh molecule i. e. L-Rhamno-S-Me and add an
additional inter-molecular charge constraint between the methyl group
of L-Rhamno-S-Me and the thiol group of cysteine (see '<------->'
above).
This is quite easy to set up once we understood how the automatic
procedure works (see
http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#25)
I would start by the approach -1-, but for sure the approach -2- is
more flexible and allows more modifications:
- do you want to add another 6-deoxy-aldose (the L-Fucose)?
-> no problem, you add the L-Fucoside as a eighth molecule in the
multi-molecule job...
> But in the end, what is deposited in the FFTopDB is the residue without the
> methyl or acetate cap, right?
R.E.D. IV will generate the mol2 files you need in the 'Mol_MM'
directory: you will need the FG2 fragment for the central fragment and
FG fragments for the two terminal ones.
Please see:
http://q4md-forcefieldtools.org/Tutorial/P2N/All-frag-Pept/listing-6mol.pdf
Coordinates for the fusion between ammonium or acetate and the
dipeptide are by now recomputed; so your FG fragments should even have
a correct geometry.
regards, Francois
> On Wed, Aug 24, 2011 at 11:38 PM, FyD <fyd.q4md-forcefieldtools.org> wrote:
>
>> Dear Yun Shi,
>>
>> > I am trying to understand how this works.
>>
>> If you look at the data available in the "F-85" R.E.DD.B. project, you
>> will find a x/tLEaP script to construct the CD-based glycopeptides as
>> well as a frcmod file for missing force field parameters with comments.
>> http://q4md-forcefieldtools.org/REDDB/projects/F-85/script1.ff
>> http://q4md-forcefieldtools.org/REDDB/projects/F-85/script3.ff
>>
>> > So instead of combining individual residues in a building-block manner,
>> as
>> > in the assignment of atomic charges for proteins with amber99sb, it is
>> > recommended to consider the ligand as a holistic molecule when
>> calculating
>> > the RESP charge?
>>
>> 'recommended'? ;-) ... Personally, I use most of the time the building
>> block approach whatever if the target 'big' molecule is a ligand or a
>> nucleic acid/protein/polysacharide.
>>
>> > I am curious that if I could do things in a building-block
>> > manner since it can potentially decrease a lot of computational time for
>> > geometry optimization.
>>
>> The building-block approach has many advantages:
>> - it potentially "decreases a lot of computational time for geometry
>> optimization" as you said.
>> - it allows rigorously defining the conformation of each
>> building-block and not to use a conformation more or less randomly
>> chosen.
>> - it allows avoiding interactions between charges group during
>> geometry optimization in gas phase.
>> - it allows the construction of analogs for the target molecule.
>> - it allows the construction of oligomers/polymers for the target molecule.
>>
>> However, it also has disadvantages:
>> - it is complex to set up when one starts, but R.E.D. has been
>> designed for this approach.
>> - errors during the charge fitting step are introduced when using the
>> building-block approach; these errors have to be minimized by
>> correctly selecting the connecting groups between the different
>> building-blocks. The statistics module available in R.E.D.
>> Server/R.E.D. IV also helps to localize/minimize these errors.
>>
>> > And when it comes to geometrical parameters, we should use GLYCAM for
>> sugar
>> > part, 99SB for standard amino acids, and GAFF for organic part?
>>
>> Yes
>>
>> - We only select 'obvious' missing force field parameters from GAFF
>> (we recompute key dihedrals), and when used we always rationalize
>> these force field parameters as it was done in the Cornell at al.
>> force field.
>>
>> - In this work, we used Amber scaling factor values for 1-4
>> non-bonding interactions for all the glycopeptide molecular systems;
>> i.e. we did not split the system into a peptide and a sugar parts.
>>
>> > BTW, could you tell me how to generate multiple conformations with
>> geometry
>> > optimization from Gaussian 09?
>>
>> You could do a conformational search - although if the building-block
>> approach is used the conformational search is quite simplified...
>> We also often modify a key dihedral to look for lowest minimum/minima.
>>
>> To create a P2N file with multiple conformations, see:
>> http://q4md-forcefieldtools.org/Tutorial/Tutorial-1.php#3
>> http://q4md-forcefieldtools.org/Tutorial/Tutorial-1.php#EXAMPLE-P2N-FILE
>>
>> To create a QM file with multiple conformations to be used in the Mode
>> 2 of R.E.D. (see
>> http://q4md-forcefieldtools.org/REDS/popup/popredmodes.php), simply
>> concatenate the different QM outputs into a single file.
>>
>> regards, Francois
>>
>> >> Dear Yun,
>> >>
>> >> > Is it technically possible to do it due diligence in the first place?
>> >> That
>> >> > is, cut the molecule into three parts as I mentioned before, use
>> GLYCAM
>> >> for
>> >> > the sugar part, 99SB for the Thr, and GAFF for modified Phe and the
>> >> > thio-glycosidic linkage. And may I then link these parts together
>> using
>> >> LEaP
>> >> > ?
>> >>
>> >> Concerning the use of GLYCAM + GAFF + Amber99SB you might be
>> >> interested by looking at the following paper:
>> >> http://www.ncbi.nlm.nih.gov/pubmed/21792425
>> >> & its corresponding R.E.DD.B. project .
>> >> http://q4md-forcefieldtools.org/REDDB/projects/F-85/ + its LEaP script:
>> >> http://q4md-forcefieldtools.org/REDDB/projects/F-85/script1.ff
>> >>
>> >> This work is about cyclodextrin based-glycopeptide and 1-4 non-bonding
>> >> interactions in GLYCAM & Amber99SB.
>> >>
>> >> Your structure is not a cyclodextrin but this work describe (i) how to
>> >> derive charges and build force field libraries for new fragments by
>> >> using R.E.D. IV and (ii) proposes new directions concerning the
>> >> treatment of 1-4 non-bonding interactions in the context of
>> >> glycopeptides.
>> >>
>> >> Finally, in the LEaP script you will find examples how to connect
>> >> organic, amino-acid and monosaccharide units...
>> >>
>> >> regards, Francois
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Received on Thu Aug 25 2011 - 23:30:02 PDT
