Dear Yun,
- When you have a peptide bond within a molecule, R1NH-COR2 you could
split this molecule into two parts R1NH-ACE & NME-COR2 (ACE = CH3CO;
NME = NHCH3; are capping groups). You use two INTRA-MCC set to zero
for these capping groups:
R.E.D.:
2 FG2 fragments LEaP
R1NH-ACE + NME-COR2 --> R1NH COR2 -----> R1NH-COR2
<=> <=>
2 INTRA-MCC = 0
- When you have a disaccharide R'-O-R", you could split it into two
monosaccharides by using an INTER-MCC set to zero between the methyl
group of the methylglycoside (building-block 1) and the chosen
hydroxyl group belonging to the second monosaccharide unit:
R.E.D.:
R'O-Me HO-R" 2 FG1 fragments LEaP
<-----> ---> R'O R" -----> R'-O-R"
1 INTERMCC = 0
by analogy, you could test:
R'S-Me HS-R"
<-----> ---------------> R'-S-R"
1 INTERMCC = 0
With these simples rules you can split your red-blue-red-green
molecule into 4 building blocks.
These have been defined some time ago; see
http://q4md-forcefieldtools.org/Tutorial/Tutorial-1.php
&
Cieplak et al. Application of the multimolecule and
multiconformational RESP methodology to biopolymers: Charge derivation
for DNA, RNA, and proteins. J. Comput. Chem. 1995, 16, 1357-1377.
With R.E.D. Server/R.E.D. IV you can generate all these fragments into
a single R.E.D. job by using the corresponding P2N files and by
defining the correct constraints during the charge fitting step.
See
http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php
&
http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#29
regards, Francois
Quoting Yun Shi <yunshi09.gmail.com>:
> Sorry that I should have attached this model molecule I want to study
> earlier.
>
> As you can see, I divide this ligand into four parts, and the parameters
> (atomic charges, bonds, angles, dihedrals, impropers) of the red (terminal)
> sugar and green ASP can be obtained from GLYCAM and 99SB respectively.
>
> But I have to include the glycosidic oxygen between two sugar rings in the
> blue thio sugar, as this glysicidic oxygen is defined in the preceding sugar
> (the blue thio sugar) instead of the succeeding sugar according to GLYCAM.
>
> I plan to use the approach -2- you mentioned (so that I don't need generate
> many conformations), but considering my specific case, I wonder why not
> using
>
> Me-O3-L-RhamnoS-Me + MeS-CH2CH(R)NH-COMe
> <----------------------> <===========>
> INTER-MCC=0 INTRA-MCC=0
>
> , and then remove the Me - Me and MeS - COMe respectively?
>
> Since the L-Rha and TRP in my case carry only one modified site compared to
> their standard counterparts, should I include charge constraints (keep the
> atomic charges) for atoms far away from the modified sites? Such as C5 and
> C6 in the thio sugar, and the entire indole ring of the modified TRP?
>
> Thank you so much!
>
> Yun
>
>
> On Thu, Aug 25, 2011 at 11:37 PM, FyD <fyd.q4md-forcefieldtools.org> wrote:
>
>> Yun,
>>
>> > Sorry, I just read the tutorial, that is, "Central fragment of a xxx".
>> >
>> > So for the modified (C-terminal reduced) amino acid, should I add a MeCO
>> at
>> > the N-terminus and MeS at the reduced C-terminus? (considering the
>> reduced
>> > C-terminus is used to link glycosidic sulfur atom).
>> >
>> > And for the sugar molecule, should I add a Me cap to 3-hydroxyl group in
>> > addition to a methyl group attached to the glycosidic sulfur? (This sugar
>> > molecule would fall into the category of central fragment of my ligand)
>>
>> ups I overlooked your problem ;-) You do not have any cysteine residue...
>>
>> Let's re-do the explanations with your terminal molecule/pseudo amino-acid:
>>
>> -1- you consider the following molecule
>>
>> Thio-L-Rhamno-CH2CH(R)NH-COMe ; R = CH2-Ph
>> <==>
>> INTRA-MCC
>>
>> You only have to set up an intra-molecular charge constraint
>> (INTRA-MCC keyword) for the COMe capping group (see <==> above).
>> See http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#15
>>
>> R.E.D. will generate a sm fragment (mol2 file) for you.
>>
>> -2- you split your molecule into two building blocks.
>>
>> L-RhamnoS-Me + HS-CH2CH(R)NH-COMe
>> <-------> <==>
>> INTER-MCC INTRA-MCC
>>
>> See http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#16
>> or http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#17
>>
>> You set up an intra-molecular charge constraint (INTRA-MCC keyword)
>> for the COMe capping group.
>> You set up an inter-molecular charge constraint (INTER-MCC keyword)
>> between the methyl group of L-RhamnoS-Me and the thiol group of your
>> pseudo terminal amino-acid.
>>
>> The approach -2- is once again more complex but more flexible...
>>
>> R.E.D. will generate a FG fragment (mol2 file) in the Mol_MM directory.
>>
>> Sorry for misunderstanding your problem in my first email.
>>
>> regards, Francois
>>
>>
>> > On Thu, Aug 25, 2011 at 9:58 AM, Yun Shi <yunshi09.gmail.com> wrote:
>> >
>> >> Thank you very much!
>> >>
>> >> 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?
>> >>
>> >> But in the end, what is deposited in the FFTopDB is the residue without
>> the
>> >> methyl or acetate cap, right?
>> >>
>> >> Yun
>> >>
>> >>
>> >>
>> >> 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 Sat Aug 27 2011 - 00:30:03 PDT
