Yun,
> And GLYCAM used different charges for alpha and beta anomers, so should I
> stick to this even if I am using the 'amber' strategy?
You do not 'need' to stick to this: you simply use two different
building blocks: one is alpha and the other is beta; in these
conditions, this is normal that by fitting to the MEP you get two
different charge values for the alpha and beta anomers...
regards, Francois
> On Mon, Sep 12, 2011 at 11:32 PM, Yun Shi <yunshi09.gmail.com> wrote:
>
>> 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 - 09:00:05 PDT
