Hi Francois,
I basically understand this approach now. But for this Rha-S-CH2-CH(R)-NH-
group, how should I deal with the N terminus? If I simply add an ACE cap to
make it Rha-S-CH2-CH(R)-NH-ACE, then how to set charge constraints? Should I
add a Met or a Hydrogen to O3 on Rha? Because CENTRAL fragments instead of
TERMINNAL fragments are needed here.
So what about
INTER-MCC=0
<======>
Rham-*OH* *Met*-O3-L-Rhamno-*SH* + *Met-*S-CH2CH(R)NH-*COMe*
<=====>
<----->
INTER-MCC=0
INTRA-MCC=0
and then remove the bolded parts.
Sorry our library does not have access to the Cieplak et al. paper.
In addition, I noted that GLYCAM06 have exactly the same charges for most
atoms in the same sugar molecule with different linkage, i.e.,
2-L-alpha-Rhamnose share identical atomic charges with 3-L-alpha-Rhamnose
except O2 and O3. However in amber99sb, every corresponding single atom of,
say TRP, would have different charges from ntTRP. I guess this may have
something to do with the charge-deriving methods, as qwt=0.0005/0.001 in
99sb VS qwt=0.01 in GLYCAM.
But then the question would be, should I set charge constraints to most
atoms on the sugar ring except the anomeric carbon and derive charges using
RESP-C2 for the sugar part, which would allow me to avoid the use of the
first Rhamnose? Or just do all charges with RESP-A1A?
Thanks a lot,
Yun
On Sat, Aug 27, 2011 at 12:16 AM, FyD <fyd.q4md-forcefieldtools.org> wrote:
> 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
>
>
>
>
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
>
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Tue Sep 06 2011 - 22:30:02 PDT
