Dear Yun,
> 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,
Yes, with a trans peptide bond:
H
Rha-S-CH2-CH(R)-N-C-Me
O
> then how to set charge constraints?
You set a single INTRA-MCC = 0 for the ACE chemical group in the P2N file.
See
http://q4md-forcefieldtools.org/Tutorial/Tutorial-3.php#15
(However in this #15 example two capping groups are added, so two
INTRA-MCC are set in the P2N file; In your case, you need to set a
single INTRA-MCC in your P2N file).
> Should I
> add a Met or a Hydrogen to O3 on Rha? Because CENTRAL fragments instead of
> TERMINNAL fragments are needed here.
So you need two L-Rhamnoside building blocks...
a perOH-thiomethyl-Rhamnoside & a perOH-O-methyl-Rhamnoside
[You could also try a different set of connecting groups between
S/O-hemiacetals (instead of S/O-acetals) and methoxy groups (i.e.
ether groups instead of hydroxyl groups).
> Sorry our library does not have access to the Cieplak et al. paper.
ok, I will send you the pdf file to your personal address (I think the
license to publish exclude the free distribution of this 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.
This has to do with the charge constraints applied during the charge
fitting step.
> 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?
Well you are right; this is the key ;-)
-1- I guess GLYCAM developers will suggest you to use something
similar to the RESP-C2 charge model; i.e. MEP computation using the
CHELPG algo. and a single RESP fitting stage using the qwt=.01
hyperbolic restraint. This means using 1.0 scaling factors for the 1-4
non-bonding interactions for the sugar part of your ligand and 1.2/2.0
for the other part. Quite complex... considering the size of your
ligand and considering that the Connolly surface algorithm is used in
MEP computation and a two RESP stage fitting approach is used for the
non-sugar part.
-2- Considering that L-Rhamnose is the 6-deoxy-L-mannose, I would
follow the approach we described .
http://www.ncbi.nlm.nih.gov/pubmed/21792425/ for all your ligand and
more general all your molecular system (in case of a Galacto
configuration I would suggest you to use the GLYCAM approach -1-).
This means 1.2/2.0 scaling factors for all the 1-4 non-bonding
interactions and using the Connolly surface algorithm in MEP
computation and a two RESP stage fitting approach for the entire
ligand. Far more simple... However, this approach has obviously to be
validated (however as it is requested for the case -1-).
regards, Francois
> 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
Received on Thu Sep 08 2011 - 00:00:03 PDT
