Hi Francois,
I am worried since I saw no atom names information in the gaussian input
file, which I used to do geometry optimization. I guess I should construct
the gaussian input file from the xxx.pdb file generated by Ante_R.E.D., then
do my geometry optimization, then submit the gaussian out file together with
xxx.p2n for charge derivation. So would there be any problem by doing so?
In addition, I have only two major conformations for my small test molecule
after QM geometry optimizations. So I wonder if I could just construct a
merged p2n file with pdb coordinates from the two major QM-optimized
conformers? I don't quite understand why R.E.D. server need QM optimization
output file.
Looking through the 'q4md-CD' paper, I feel it kind of counter-intuitive to
mix GLYCAM04 geometrical parameters with atomic charges from 'Amber'
strategy, which however, reproduced experimental data so well. But now I
feel like that the RESP charges come hand-in-hand with the scaling factor,
and I guess using the amber scaling factors is the major reason that your
charge-derivation approach is successful.
Since my molecule (the thio-glycosidic part) has no reference to look for
experimental data to compare, what would be a simple experiment to carry out
to validate my parameters? Or just try fitting them to QM calculations?
By the way, what do you mean by " 'recompute' key dihedrals" when taking
parameters from GAFF? And which are key dihedrals?
Thanks,
Yun
On Wed, Sep 7, 2011 at 11:57 PM, FyD <fyd.q4md-forcefieldtools.org> wrote:
> 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
>
>
>
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Received on Tue Sep 13 2011 - 00:00:02 PDT
