certainly it's possible, my comments were just that it was not typical and
was not in the standard database.
my lab recently reported simulations with protonated C-terminal carboxyl,
which needed new parameters that we would share if anyone wants them:
Evaluating the Performance of the ff99SB Force Field Based on NMR Scalar
Coupling Data
Lauren Wickstrom, Asim Okur and Carlos Simmerling
Biophysical Journal, Volume 97, Issue 3, 853-856, 5 August 2009
doi:10.1016/j.bpj.2009.04.063
On Tue, Apr 20, 2010 at 7:46 AM, Dmitry Nilov <nilovdm.gmail.com> wrote:
> N-terminal is deprotonated at pH 7 at least in N-terminal hydrolases such
> as
> penicillin acylase. Thus, neutral N-terminal is possible.
>
> On Tue, Apr 20, 2010 at 3:36 PM, Carlos Simmerling <
> carlos.simmerling.gmail.com> wrote:
>
> > at normal pH one does not expect to see protonated C terminus or
> > deprotonated N terminus. Normally if you want a neutral terminal, a
> > blocking
> > group is added in the experiment (acetylating or amidating the end). so
> how
> > you proceed depends on what experimental conditions you are trying to
> > reproduce. If you really think you have an unusual protonation state for
> a
> > terminal group, you need to develop your own residue. You might check
> > recent
> > literature on constant pH simulations (such as from the Roitberg lab) to
> > see
> > if they included termini as well as the ionizable side chains.
> >
> > On Tue, Apr 20, 2010 at 7:27 AM, Andrew Voronkov <drugdesign.yandex.ru
> > >wrote:
> >
> > > Yes, I have found none in manual and I wonder what is generally done in
> > > this case and if this was somehow considered.
> > >
> > > 20.04.10, 14:43, "Dmitry Nilov" <nilovdm.gmail.com>:
> > >
> > > > Hello! There are no standard uncharged N-terminal and C-terminal
> > residues
> > > in
> > > > Amber.
> > > >
> > > > On Tue, Apr 20, 2010 at 2:23 PM, Andrew Voronkov wrote:
> > > >
> > > > > A bit more general question. For example I've got pKa which
> > > correspond to
> > > > > protonated state of amido group of N-terminal amino acid or
> > > deprotonated
> > > > > state of C-term carboxylic group. How is possible in amber to
> > > discriminate
> > > > > by names between protonated\deprotonated C- and N- terminal amido
> > and
> > > > > carboxylic groups?
> > > > >
> > > > > Best regards,
> > > > > Andrew
> > > > >
> > > > > 16.04.10, 15:05, "Dean Cuebas" :
> > > > >
> > > > > >
> > > > > > > From: Andrew Voronkov
> > > > > > > Reply-To: AMBER Mailing List
> > > > > > > Date: Fri, 16 Apr 2010 13:17:32 -0500
> > > > > > > To: AMBER Mailing List
> > > > > > > Subject: Re: Re: [AMBER] how is pH treated in Amber - other
> > than
> > > > > constant pH
> > > > > > > simulations
> > > > > > >
> > > > > > > Thank you that is actually what I do. The prediction by H++
> > > server
> > > > > with
> > > > > > > isntant protonation, just wondered if this fits to Amber pH
> > > strategy
> > > > > without
> > > > > > > constant pH. As to H-bonds from Molprbity - aren't H bonds
> > > supposed to
> > > > > result
> > > > > > > mostly from MD simulations?
> > > > > >
> > > > > > I might have been a bit confusing here...
> > > > > > What I meant was that the way that molprobity (the reduce app)
> > adds
> > > > > > hydrogens to especially histidine tends to be better than H++
> in
> > > that it
> > > > > > assigns delta versus epsilon tautomers. In fact, I've only seen
> > H++
> > > > > > assigning uncharged histidines as epsilon, whereas reduce will
> > > assign
> > > > > delta
> > > > > > and visually it is very clear that a strong H-bond from another
> > > residue
> > > > > to
> > > > > > the delta H of a particular HIS is clearly preferred over an
> > > epsilon
> > > > > without
> > > > > > such h-bond stabilization. On the other hand, H++ pka
> predictions
> > > > > usually
> > > > > > help with deciding to have protons on both delta and epsilon
> > > nitrogens.
> > > > > >
> > > > > > Of course you can go the whole mile and do an iterative process
> > > where
> > > > > you
> > > > > > now do MD on your first set of protonation predictions and then
> > > resubmit
> > > > > to
> > > > > > molprobity and H++ to see if you converge on a stable set of
> > > > > predictions.
> > > > > >
> > > > > > Dean
> > > > > > > Btw as I can see many parameters like Z-score significantly
> > > improve
> > > > > after MD
> > > > > > > even against X ray structures.
> > > > > > >
> > > > > > > Best regards,
> > > > > > > Andrew
> > > > > > >
> > > > > > > 16.04.10, 11:53, "Dean Cuebas" :
> > > > > > >
> > > > > > >>
> > > > > > >> Dear Andrew,
> > > > > > >>
> > > > > > >> I have found the best approach to protonating my proteins
> is
> > to
> > > use
> > > > > the pKa
> > > > > > >> predictions of the H++ server in conjunction with the
> > superior
> > > > > H-bonding
> > > > > > >> prediction of reduce at the Molprobity server.
> > > > > > >>
> > > > > > >> 1) Use Molprobity to flip Asn, Gln, His residues as needed,
> > > since
> > > > > MOST
> > > > > > >> proteins from XRC need fixing in this regard.
> > > > > > >> 2) Save the flipped but NOT protonated pdb to use as input
> to
> > > the
> > > > > H++ server
> > > > > > >> for pKa predictions.
> > > > > > >> 3) Continue with the Molprobity server to maximize
> H-bonding
> > > > > possibilities
> > > > > > >> and protonate the protein.
> > > > > > >>
> > > > > > >> 4) Using visual inspection of the molprobity output for
> > h-bond
> > > and
> > > > > clashes,
> > > > > > >> and the pKa predictions of H++ you can come to some
> > reasonably
> > > > > confident
> > > > > > >> expectations, especially with regards to the correct state
> of
> > > > > histidine,
> > > > > > >> picking the correct HID or HIE neutral annular tautomer, or
> > the
> > > > > protonated
> > > > > > >> HIP.
> > > > > > >>
> > > > > > >> Realize that constant pH cannot be used with explicit water
> > MD,
> > > so
> > > > > if you
> > > > > > >> use a water box, you should do the above.
> > > > > > >>
> > > > > > >> Hope this helps!
> > > > > > >>
> > > > > > >> Dean
> > > > > > >>
> > > > > > >>
> > > > > > >>> From: Carlos Simmerling
> > > > > > >>> Reply-To: AMBER Mailing List
> > > > > > >>> Date: Fri, 16 Apr 2010 11:10:42 -0500
> > > > > > >>> To: AMBER Mailing List
> > > > > > >>> Subject: Re: [AMBER] how is pH treated in Amber - other
> than
> > > > > constant pH
> > > > > > >>> simulations
> > > > > > >>>
> > > > > > >>> simulations in amber are either constant pH or constant
> > > protonation.
> > > > > > >>> default protonations are reasonable for the isolated amino
> > > acids,
> > > > > but
> > > > > > >>> pka shifts may occur in proteins. it is possible to
> calculate
> > > pkas
> > > > > for
> > > > > > >>> the initial structure, assign protonation states, and keep
> > > them.
> > > > > this
> > > > > > >>> is ok as long as there are not conformation dependent pka
> > > changes
> > > > > that
> > > > > > >>> cross your pH.
> > > > > > >>>
> > > > > > >>> On 4/16/10, Andrew Voronkov wrote:
> > > > > > >>>> Dear Amber users,
> > > > > > >>>> when I am looking for questions about pH and Amber I get
> > > mostly
> > > > > information
> > > > > > >>>> about constant pH simulations. But what pH is supposed
> to
> > be
> > > by
> > > > > default,
> > > > > > >>>> without constant pH simulations? Just neutral or what it
> > > depends
> > > > > from?
> > > > > > >>>> As I understand in Amber pH is mostly set by protonation
> > > state of
> > > > > the
> > > > > > >>>> molecules, so if not going to constant pH simulation I can
> > > > > approximately
> > > > > > >>>> imitate some pH by setting corresponding protonation state
> > > > > distribution of
> > > > > > >>>> amino acids. If physiological pH is required for protein
> > > simulation
> > > > > what
> > > > > > >>>> can
> > > > > > >>>> be general recommendation here - instant pH or default pH
> > > > > treatment?
> > > > > > >>>>
> > > > > > >>>> Sincerely yours,
> > > > > > >>>> Andrew
> > > > > > >>>>
> > > > > > >>>> _______________________________________________
> > > > > > >>>> AMBER mailing list
> > > > > > >>>> AMBER.ambermd.org
> > > > > > >>>> http://lists.ambermd.org/mailman/listinfo/amber
> > > > > > >>>>
> > > > > > >>>
> > > > > > >>>
> > > > > > >>> --
> > > > > > >>>
> > > ===================================================================
> > > > > > >>> Carlos L. Simmerling, Ph.D.
> > > > > > >>> Professor, Department of Chemistry
> > > > > > >>> CMM Bldg, Room G80 Phone: (631) 632-1336 Fax:
> > > 632-1555
> > > > > > >>> Stony Brook University E-mail:
> > > > > carlos.simmerling.gmail.com
> > > > > > >>> Stony Brook, NY 11794-5115 Web:
> http://www.simmerlinglab.org
> > > > > > >>>
> > > ===================================================================
> > > > > > >>>
> > > > > > >>> _______________________________________________
> > > > > > >>> 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
> > > > > > >>
> > > > > > >>
> > > > > > >
> > > > > > > _______________________________________________
> > > > > > > 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
> > > > > >
> > > > > >
> > > > >
> > > > > _______________________________________________
> > > > > AMBER mailing list
> > > > > AMBER.ambermd.org
> > > > > http://lists.ambermd.org/mailman/listinfo/amber
> > > > >
> > > >
> > > >
> > > >
> > > > --
> > > > Dmitry Nilov,
> > > > Lomonosov Moscow State University
> > > > _______________________________________________
> > > > 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
> > >
> > _______________________________________________
> > AMBER mailing list
> > AMBER.ambermd.org
> > http://lists.ambermd.org/mailman/listinfo/amber
> >
>
>
>
> --
> Dmitry Nilov,
> Lomonosov Moscow State University
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
>
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Received on Tue Apr 20 2010 - 06:30:02 PDT
