Hello I am just resending my last post.
Thank you in advance for commenting at least some of my points.
Best wishes,
Marek
Dne Fri, 27 Jan 2017 01:02:29 +0100 Marek Maly <marek.maly.ujep.cz>
napsal/-a:
> Hello Junmei,
>
> first of all thanks a lot for complex answer !
>
> Nevertheless I have some more comments/questions and I would be grateful
> for your additional comments.
>
> #1
> As we agreed GAFF2 is a "bit less" compatible with the actual AMBER
> protein, lipid, nucleid acid
> force fields, than GAFF, which is clearly connected with the quite
> different way of parameters (at least some) generation. So as this
> situation is not ideal for simulations of mixed systems (drug/protein,
> drug/lipid, drug/nucleid acid), would be probably good idea to
> reparameterize in the future also the AMBER bio-force-fields using the
> same strategy which was used for GAFF2, especially if extensive
> evaluation of GAFF2 ff will in many concrete systems show better results
> (comparing with experiment) than actual version of GAFF. Do you agree ?
>
> #2
> What is your opinion regarding mixing of GAFF2 with the actual AMBER
> bio-force fields ? I think that here the most important is, how much
> are given force fields compatible in nonbond terms parameterisation
> (vdw, electrostatic) and this point is probably OK here.
> I did not checked this in detail but for example vdw terms for c3 are
> pretty similar in both ff.
>
> GAFF
> c3 1.9080 0.1094 OPLS
> GAFF2
> c3 1.9069 0.1078
>
> You wrote that you are doing a set of evaluation for GAFF2 now, so I
> assume that part of this evaluation was for sure devoted to simulation
> of mixed systems drug/(biomolecule) where differences in using GAFF2 or
> GAFF (for drug) was carefully analyzed (conformations of the drug on the
> binding site, conformation of molecular complex, binding energy) and
> eventually compared with experiment.
>
> It is clear to me, that you cannot say here any details about those
> evaluation results before they are published, but can you at least tell
> us, just as far as you know now, if using of GAFF2 in combination with
> the actual AMBER bio-force fields is really safe ? I mean if you, based
> on your actual knowledge, can recommend it or if you rather recommend to
> use the latest version
> (1.8) of GAFF ?
>
> #3
> This change of parameterization strategy unfortunatelly creates some
> incompatibility problem (I hope not so big) also when one would like to
> add new parameters for new atoms/atom types to GAFF2 using paramfit
> routine as it only allows to fit using energies or forces. I think that
> more compatible will be now (to add new parameters to GAFF2) to use here
> forces fitting which is unfortunately still available only for
> commercial gaussian outputs.
> What is your opinion here ? Which are plans here for the near future ?
> Some extension to use QM vibration frequencies for fitting or at least
> to make accessible force fitting for those who uses free GAMESS instead
> GAUSSIAN ? BTW you wrote "The ab initio frequencies were obtained at
> B3LYP/6-31G* level." To be frank I would expect a little more accurate
> approach, but I am definitely not specialist here and you probably found
> that this is quite enough comparing to experimental frequencies where
> available. But my question is, if one uses paramfit to add new
> parameters it is automatically the best choice also B3LYP/6-31G* or if
> I use a bit more precise theory like MP2/6-31G** it is also OK or even
> better ?
>
> #4
> Regarding that c3-c3 bond I did some ff searching. Mostly I found K
> value close to GAFF value (i.e. arround 300). Here I would like to
> emphasize GLYCAM case:
>
> GLYCAM6j
> Cg-Cg 310.0 1.520 Butane (gauche, and trans)
>
> where the K is 310 kcal/mol/A*A (so similar to GAFF and different from
> GAFF2 value) in spite
> the fact that in AMBER16 manual page 41 we can read:
>
>
> "The GLYCAM-06 force field has been validated against quantum mechanical
> and
> experimental properties, including: gas-phase conformational energies,
> hydrogen bond energies, and vibrational frequencies; solution-phase
> rotamer populations (from NMR data); and solid-phase vibrational
> frequencies and crystallographic unit cell dimensions."
>
> So this force field was clearly validated also using "vibrational
> frequencies" and still we have here c3-c3 K = 310 which is so much
> different from GAFF2 value (232.52) which was derived using vibrational
> frequencies fitting. Do you have any explanation here ?
>
> On the other hand I found that in CHARMM they are very close to GAFF2 K
> value:
>
> CHARMM36
> -----------------------
> CARBOHYDRATES
> CC311 CC311 222.50 1.500 ! par22 CT1 CT1 ( CC311 generic
> acyclic CH carbon)
> CC312 CC312 222.50 1.485 ! adm 11/08, glycerol ( CC312 CH carbon
> in linear polyols)
> CC321 CC321 222.50 1.530 ! par22 CT2 CT2 ( generic acyclic CH2
> carbon (hexopyranose C6) )
>
>
> PROTEINS
> CT2 CT2 222.500 1.5300 ! ALLOW ALI (CH2)
> CT3 CT2 222.500 1.5280 ! ALLOW ALI (CH3)
>
> NUCLEIC ACIDS
> CN8 CN8 222.50 1.528 !Alkanes, sacred (Nucleic acid carbon
> (equivalent to protein CT2))
> CN8 CN9 222.50 1.528 !Alkanes, sacred (Nucleic acid carbon
> (equivalent to protein CT3))
>
> GENERAL FF
> CG321 CG321 222.50 1.5300 ! PROT alkane update, adm jr., 3/2/92
>
>
> --------------------------
>
> And for example this sentence from the basic CHARMM article:
>
> "Bond, valence angle, Urey-Bradley, improper and torsion
> force constants are based on MP2/6-31G(d) vibrational
> spectra."
>
> clearly explain this similarity. To be frank after I found this I
> started to trust a little more in GAFF2 than before as CHARMM is for
> sure not a bad force field :))
>
> But anyway here is nicely seen compatibility of the equivalent atomtypes
> across the all CHARMM specialised ff (carbohydrates, proteins, nucleid
> acids, general ff) which was so nicely seen also in AMBER before GAFF2
> appeared :))
>
>
> #5
> It is "very nice" that in Amber manual (page 33) is recommendation to use
> GAFF2 for organic molecules/ligands, but to be frank I did not find
> any information about this new
> force field in manual.
>
> In chapter "15.6.2. New Development of GAFF" there are clearly
> described just some last corrections to GAFF.
>
> So in my opinion would be appropriate to add here at least some short
> info similar to that which is
> written at the end of the gaff2.dat file, which I additionally found
> just by accident.
>
> So thank you in advance very much for your eventual additional comments.
>
> Best wishes,
>
> Marek
>
>
>
>
>
> Dne Thu, 26 Jan 2017 19:04:30 +0100 Junmei Wang <junmwang.gmail.com>
> napsal/-a:
>
>> In GAFF, the bond stretching and bond angle bending force constants come
>> from protein/nucleic acid force fields (FF94, FF99) whenever possible.
>> For
>> those not having any counterparts in FF94/FF99, we used a set of
>> empirical
>> formulae (please refer to the GAFF paper) to calculate the force
>> constants. The parameters of those formulae were derived to reproduce
>> the
>> existing force constants in FF94/FF99.
>>
>> However, in GAFF2, we adopted a different philosophy to derive those
>> parameters (26 in total). We optimized those parameters to minimize the
>> differences between the calculated MM frequencies and the ab initio ones
>> (the training set has 572 small molecules and 22407 frequencies in
>> total).
>> We also tested the best parameter set with a large test set (711
>> molecules,
>> 29000 frequencies). The ab initio frequencies were obtained at
>> B3LYP/6-31G*
>> level. We could reduce the RMS errors from 120 cm-1 for GAFF to 60 cm-1
>> for
>> both the training and test sets.
>>
>> We are now doing a set of evaluation for GAFF2, which will be a part of
>> the
>> GAFF2 paper. I agree with you that GAFF is more consistent with the
>> current
>> protein/nucleic acid force fields. And the difference between GAFF and
>> GAFF2 for c3-c3 is very big.
>>
>> Hopefully this can help you to choose a proper version of GAFF force
>> field
>> in your study.
>>
>> Junmei
>>
>> On Tue, Jan 24, 2017 at 7:24 PM, Marek Maly <marek.maly.ujep.cz> wrote:
>>
>>> Thank you !
>>>
>>> BTW that difference in c3-c3 force constant GAFF vs GAFF2 is really big
>>> 300.9 vs 232.52 I would say. To be frank I am a bit confused with such
>>> a
>>> big change moreover in such basic/common atomtype bonding term.
>>> This indicates that methodology and/or set of molecular fragments which
>>> were used for fitting in GAFF2 case had to be quite different from
>>> methodology or mol. fragments used in GAFF case.
>>>
>>> I am also a bit confused with the fact that the same term in actually
>>> recommended protein force field ff14SB has still force constant close
>>> to
>>> old GAFF value:
>>>
>>> CT-CT 310.0 1.526 JCC,7,(1986),230; AA, SUGARS
>>>
>>> So old GAFF seems to me to be a more compatible with ff14SB from this
>>> point of view than with the new GAFF2, which is a bit strange or not ?
>>>
>>> BTW the same trend holds if we compare here GAFF/GAFF2 with LIPID14 ff.
>>>
>>> cA-cA 303.1 1.5350 Lipid11 v1.0 (GAFF c3-c3)
>>> cD-cD 303.1 1.5350 Lipid14 v2.0 (GAFF c3-c3)
>>>
>>> again we are much closer here to GAFF values.
>>>
>>> The same trend holds for vdW terms:
>>>
>>> GAFF
>>> c3 1.9080 0.1094 OPLS
>>> GAFF2
>>> c3 1.9069 0.1078
>>> FF14SB (parm10)
>>> CT 1.9080 0.1094 Spellmeyer
>>> LIPID14
>>> cA 1.9080 0.1094 OPLS
>>> cD 1.9080 0.1094 OPLS
>>>
>>>
>>> So it seems that if one is going to simulate some heterogenous system
>>> (e.g. protein + drug) it should be more suitable to use still old GAFF
>>> (not the new GAFF2) as GAFF is clearly more compatible
>>> with bio-force-fields than GAFF2 or am I wrong here ?
>>>
>>>
>>> Best wishes,
>>>
>>> Marek
>>>
>>>
>>>
>>> Dne Tue, 24 Jan 2017 19:44:34 +0100 David Case <david.case.rutgers.edu>
>>> napsal/-a:
>>>
>>> > On Tue, Jan 24, 2017, Marek Maly wrote:
>>> >>
>>> >> I have technical question regarding QM methods used in GAFF2
>>> >> development.
>>> >
>>> > cc-ing to Junmei Wang, who doesn't always follow the mailing list.
>>> Note
>>> > that
>>> > you may need to wait for the paper on GAFF2 to be published...
>>> >
>>> > ...dac
>>> >
>>> >>
>>> >> In Amber16 manual, page 286, there is written:
>>> >>
>>> >> "We have performed B3LYP/6-31G* optimization for 15 thousands
>>> >> marketed or
>>> >> experimental ..."
>>> >>
>>> >>
>>> >> So B3LYP/6-31G* is here QM method used to obtain optimized molecular
>>> >> structures (low energy
>>> >> conformations) from which equilibrium geometrical terms (eq. bond
>>> >> lengths,
>>> >> eq. angles) were obtained
>>> >> and so in some cases old GAFF values were updated.
>>> >>
>>> >>
>>> >> But in GAFF2, comparing to GAFF, changed clearly also some force
>>> >> constants.
>>> >> As an example I can mention c3-c3 bond:
>>> >>
>>> >>
>>> >> In GAFF
>>> >> c3-c3 300.9 1.5375 SOURCE1_SOURCE5 88072 0.0058
>>> >>
>>> >> In GAFF2
>>> >> c3-c3 232.52 1.538 SOURCE1_SOURCE5 88072 0.0058
>>> >>
>>> >>
>>> >> My question is, which QM methodology was used to derive (perhaps
>>> using
>>> >> paramfit ?) new GAFF2 bond, angle or dihedral force constants ?
>>> >>
>>> >> I assume, that since here we need just to calculate for each
>>> >> conformation
>>> >> only it's
>>> >> energy (no optimization) and since we also need to obtain reliable
>>> >> force
>>> >> constants (hence we need accurate QM energies) some more accurate
>>> method
>>> >> was probably used like MP2/6-31G** , MP3/6-31G** etc. to derive QM
>>> >> energies. Am I right ?
>>> >>
>>> >> So thank you in advance for QM methodology specification used in
>>> GAFF2
>>> >> for
>>> >> force constants
>>> >> derivation.
>>> >>
>>> >> Best wishes,
>>> >>
>>> >> Marek
>>> >>
>>> >
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Received on Sat Feb 04 2017 - 19:30:02 PST
