If you can send me the .prepi file you use for your modified Cysteine and
the tleap input you used to make your dipeptide, I can show you what I
mean. You need to change N, H, C, and O of the Cysteine to match the
charges used by ff14SB, as seen in amino12.lib. I'd suggest changing the
CA and HA atoms as well. This will almost certainly change the net charge
on the residue, so to conserve the (-1) you need to make compensatory
alterations to the charges on other atoms. If you can do this with modest
changes to the sulfur and CB atoms, then I'd say you're in good shape to
roll without a more aggressive charge refit. If you want a direct
HF/6-31g* charge fit for this molecule, however, that's not a technical
challenge (it's a big molecule, but a small enough basis set and only
involves electron density computation at the self-consistent field level).
Dave
On Thu, Nov 3, 2016 at 12:39 PM, Aditya G Rao <aditya.grao.mail.huji.ac.il>
wrote:
> Dear Carlos and David,
> Thanks a lot for the suggestions and the explanation!
>
> .David: What exactly do you mean by, " As needed you may distribute the
> excess charge this imparts to the sulfur and the first carbon on the
> pyrrole to get the net charge back to (-1)"?
>
> Thanks in advance!
> Aditya
>
>
> On Wed, Nov 2, 2016 at 10:44 PM, David Cerutti <dscerutti.gmail.com>
> wrote:
>
> > ^ Agree with Carlos, the interface between parameter sets should be
> > minimal. This is what I was getting at further down in my novella--take
> > ff14sb atom types for everything up to perhaps the sulfur on the side
> > chain. Now if we can retain the charges up to CB (type 2C) we can ensure
> > that the ff14sb backbone behavior (which is where the most effort has
> been
> > done) stays put. That's what we can focus on now. First, reference
> > amino12.lib in the $AMBERHOME/dat/leap/lib directory and mirror the
> charges
> > for ACE, NME, and the modified CYS up through CB. As needed you may
> > distribute the excess charge this imparts to the sulfur and the first
> > carbon on the pyrrole to get the net charge back to (-1).
> >
> > To get the best parameters for ff14sb you will need to refit charges on
> the
> > pyrrole group and sulfur while retaining the other charges that
> correspond
> > to atoms ff14sb does describe. I wouldn't recommend trying to map the
> > pyrrole atom types to ff14sb equivalents: that thing has chemical groups
> > that aren't in proteins, which puts you in a different ball park. As
> soon
> > as you need new atom types, they might as well be called "plain",
> salted",
> > and " honey roasted," so the goal here is to invest an appropriate amount
> > of effort to make something compatible with the rest of your protein.
> The
> > central dogma of ff14sb is "Hartree Fock 6-31g* charges, with bonded
> > parameters to mimic a vacuum phase MP2 / cc-pvTZ potential energy
> surface"
> > and that's what we'll do.
> >
> > One thing I didn't realize when I first replied is that your modified
> amino
> > acid is BIG. The first capability we need is to be able to make
> plausible
> > conformations of your nonstandard residue. Cysteine covalently bonded to
> > not just one ring system but a macrocycle of four! This is going to
> create
> > a challenge, but what it means is that you may want to trim away the
> excess
> > before trying new parameter development. *My advice would be this: take
> > bond and angle parameters from our libraries, decide on charges for the
> big
> > system, then create a stripped-down, tiny system and try to develop the
> > torsion parameters for the pyrrole :: ethanethiol interface.* In what
> > follows I'm providing detailed instructions to carry out that idea.
> >
> > First, take bond and bond angle parameters straight from ff14SB or GAFF,
> > using Carlos's logic: these parameters are derived prior to charge
> fitting
> > and can, in most protocols, be taken as given. They're also more
> > consistent across different atom types ({2C, CT, 3C}-CT-N, etc.)--the
> > different atom types largely come from our efforts to get increasingly
> > accurate torsions in slightly different chemical situations, but when we
> do
> > that we typically just clone the bond and bond angle parameters from
> their
> > root types (2C, 3C, and CX are all from CT). Just find the best matches
> > you can based on your chemical intuition, probably based on the ff14SB
> > methionine residue, and apply the stiffness and equilibrium parameters to
> > the new atom types at the pyrrole :: SG-CB interface.
> > Next, charges: if after reassigning the charges of the Cysteine up to SG,
> > you only need to change the charge of that sulfur by 0.1e to maintain the
> > integer net charge, I think you're set. (The charge on sulfur is never
> > well resolved by our methods--the thing's got quadrupoles that our
> > nuclear-centered charges simply can't do very well, so R-S-R' sulfur
> atoms
> > in methionine and other situations always get assigned very small charges
> > because the least squares solution is to give it no significant monopole,
> > forfeiting whatever higher order multipoles would be better.) Otherwise,
> if
> > you can find out how to make the RED server give you the charges you need
> > for the SG and nearest atoms on the tetrapyrrole, you're set. If neither
> > of those solutions works, I can hit it with mdgx and see about getting
> you
> > a reasonable charge model directly from HF/6-31g*.
> >
> > Finally, the torsion parameters: for this, you should excise one pyrrole
> > ring from your macrocycle, put CH3 blocking groups on either end where
> the
> > macrocycle got cut, and attach -S-CH2-CH3 to the other side. Then, do
> the
> > same trick of assigning ff14SB atom types to the S-CH2-CH3 atoms (i.e.
> use
> > 2C for the carbon of CH2, CX for the carbon of CH3, and H1 for all
> > hydrogens on CH2 or CH3) and the atom types of your larger Cys-Pyrrole
> > system for the pyrrole ring. Once you have that small molecule, just
> > assign it the standard AM1-BCC charges (again, I'm counting on the sulfur
> > getting a pretty small, flat charge asssignment). And keep the bond and
> > bond angle assignments from your larger Cys-pyrrole, but set the torsion
> > amplitudes involving the sulfur to zero (you're going to make a new
> frcmod
> > for this representation of the linker system in the same way it seems you
> > have for your Cys-pyrrole already). Now you've got a model system which
> > can move in the ways you need to see the joint between your larger
> Cysteine
> > and pyrrole moving. Once you've got that, I think the easiest solution
> is
> > to use the new mdgx routines to generate a handful of conformations
> (about
> > 60 I'd guess), and computations at the MP2/cc-pvTZ level will take about
> an
> > hour each on a single CPU to get their single point energies--an
> afternoon
> > with a couple of machines. With the conformations of your test system
> and
> > their single point energies in hand, it is a five minute exercise to fit
> > the torsion parameters appropriate for the links between the ff14SB and
> > GAFF components of your system.
> >
> > Last, you collect all of these bond, bond angle, and torsion parameters
> > into a frcmod and take the charges and ff14SB/GAFF atom types in your
> > .prepi or .lib file for the full cys-pyrrole, and you're ready to do your
> > simulation.
> >
> > Keep in touch, I'll do what I can to help.
> >
> > Dave
> > _______________________________________________
> > AMBER mailing list
> > AMBER.ambermd.org
> > http://lists.ambermd.org/mailman/listinfo/amber
> >
>
>
>
> --
> Aditya G. Rao
> PhD Student
> Fritz Haber Research Center for Molecular Dynamics
> Institute of Chemistry, HUJI
> Givat Ram, Jerusalem, Israel
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Received on Thu Nov 03 2016 - 10:30:02 PDT
