From: Chitrak Gupta (
Date: Wed Oct 21 2015 - 10:45:08 CDT

Hi Bryan,

Thanks a lot for the suggestions.


On Tue, Oct 20, 2015 at 4:34 PM, Bryan Roessler <> wrote:

> Hi Chitrak,
> Yes, I do believe that is a proper methodology. Just remember that as you
> delete bad water interactions, there is less QM data to guide the
> optimizer, so if you have a lot of waters flying away it might be
> worthwhile to reoptimize the geometry and rerun the water interaction
> calculations to see if you can resolve some of the steric problems.
> Bryan
> *Bryan Roessler | Graduate Research Assistant*
> UAB | The University of Alabama at Birmingham
> * <>*
> Knowledge that will change your world
> On Mon, Oct 19, 2015 at 10:59 AM, Chitrak Gupta <>
> wrote:
>> Hi Bryan and Christopher,
>> Thanks for this discussion, cleared up some of the doubts I had.
>> So, to make sure I got this right......I should start by optimizing water
>> for any atom that should in principle have water interaction, correct? And
>> then if they are flying out, just not include the log file of those waters
>> in further calculation, is that what you suggested?
>> Best regards,
>> Chitrak.
>> On Mon, Oct 19, 2015 at 10:50 AM, Mayne, Christopher G <
>>> wrote:
>>> Bryan,
>>> Apologies for a late reply; I just returned from international travels
>>> this morning.
>>> Your own suggested answer is quite on target, and it sounds like you
>>> have a pretty good handle on what is going on at this stage of the
>>> parameterization.
>>> Regards,
>>> Christopher Mayne
>>> On Oct 19, 2015, at 4:45 PM, Bryan Roessler <> wrote:
>>> I'm going to take a stab and try to answer my own question based on some
>>> further observations.
>>> I believe that it is necessary to remove any waters that do not reach a
>>> proper minimized state (for instance if they fly out of the Gaussian
>>> simulation). It is best to try and include as many water interaction target
>>> files as possible for the fragment (even for atoms that have predefined
>>> charges), but if some of them skew the optimization results (for instance,
>>> if they are not near the energy objective in COLP), then it is best to
>>> reduce their weighting in the calculation or to remove them altogether.
>>> Following these guidelines I have been able to get realistic optimized
>>> charges near the CGenFF predictions.
>>> If I am in error, please let me know.
>>> Thanks,
>>> Bryan
>>> *Bryan Roessler | Graduate Research Assistant*
>>> UAB | The University of Alabama at Birmingham
>>> *
>>> <>*
>>> Knowledge that will change your world
>>> On Fri, Oct 16, 2015 at 10:01 AM, Bryan Roessler <>
>>> wrote:
>>>> Christopher,
>>>> Thank you very much for the reply. I should have included a second,
>>>> related question in my original query: since I am not going to include the
>>>> predefined atoms in the charge optimization step, is it still necessary to
>>>> calculate the individual water interactions for those atoms and include
>>>> them as input in the optimization?
>>>> Because it is necessary to include the known atoms from the bonded
>>>> residue, the complexity of the fragment also increases (~35 atoms total).
>>>> As a result, I've found that some of the waters will fly out of the
>>>> Gaussian optimization, presumably due to steric quantum interactions with
>>>> the surrounding atoms. I know that the preferred solution is to reduce the
>>>> complexity of the fragment by breaking it down further into its molecular
>>>> components (between aliphatic carbons) but I've found that the partial
>>>> charges that are assigned using this method do not reflect the
>>>> intermolecular charges well (possibly because the fragment contains an
>>>> ester). I think it is better to keep the fragment together as long as it is
>>>> OK to remove some of the errant water interaction calculations from the
>>>> optimization. What I don't entirely understand is if the water interactions
>>>> can be removed from the initial calculation (and thus not reflected in the
>>>> single-point energies of the entire fragment? I don't know) or need to be
>>>> removed only from the optimization step so that those atoms are still
>>>> included in the single-point calculations of the entire fragment.
>>>> In my trial and error, I have tried to calculate only the water
>>>> interactions for the atoms without existing FF charges, however when I
>>>> perform the optimization using this method, the charges on the atoms tend
>>>> to drift towards an integer charge.
>>>> Thanks again,
>>>> Bryan
>>>> *Bryan Roessler | Graduate Research Assistant*
>>>> UAB | The University of Alabama at Birmingham
>>>> *
>>>> <>*
>>>> Knowledge that will change your world
>>>> On Fri, Oct 16, 2015 at 2:50 AM, Mayne, Christopher G <
>>>>> wrote:
>>>>> Bryan,
>>>>> Apologies for a delayed response; I have been traveling
>>>>> internationally.
>>>>> Yes, it is generally a good idea to include enough of the known atoms
>>>>> to cover the connection between known and unknown parameters. ffTK is
>>>>> designed so that it is easy to optimize a subset of parameters — in this
>>>>> case, retain the known parameters and optimize only the missing ones.
>>>>> For the specific case of charges, the typical method used is:
>>>>> 1) Set any “known” charges in the PSF file.
>>>>> 2) When setting the Charge Constraints (Opt. Charges -> Charge
>>>>> Constraints -> Charge Group) simply remove the known atoms from the
>>>>> constraints box.
>>>>> —> This process will optimize any atoms contained within the charge
>>>>> constraints while fixing the charge on the atoms that are not included in
>>>>> the box.
>>>>> When analyzing the optimization output, the raw objective function is
>>>>> not particularly informative. The COLP tool (available from Opt. Charges
>>>>> -> Results -> Open COLP) allows users to deconvolute the objective function
>>>>> and inspect each of the contributing terms. This allows you to judge which
>>>>> terms contribute the most to the objective function, and to identify
>>>>> problematic atoms.
>>>>> Regards,
>>>>> Christopher Mayne
>>>>> On Oct 13, 2015, at 9:08 PM, Bryan Roessler <> wrote:
>>>>> Hello,
>>>>> When parameterizing novel molecular fragments that will eventually be
>>>>> bonded to a residue with an existing forcefield, it is necessary to
>>>>> incorporate some of the atoms near the bond from the residue with existing
>>>>> forcefields that contribute to the dihedral, angle and bond parameters in
>>>>> the QM/MM optimization scheme.
>>>>> Is it then suggested that when performing the charge optimization step
>>>>> in fftk, I maintain the charges on those overlapping atoms as they exist in
>>>>> the CHARMM ffs as best as possible? In other words, should I create an
>>>>> upper and lower bound (so that the optimizer still has some 'play') that
>>>>> are very near the charge values on those atoms provided in the existing
>>>>> forcefield? Or should I let all of the charges optimize independently of
>>>>> the existing forcefield charge parameters?
>>>>> When I allow all of the charges to optimize without strict bounding, I
>>>>> can attain a total objective that is very near zero after several iterative
>>>>> optimization passes. However, when I loosely 'fix' the charges of some of
>>>>> the overlapping atoms that already exist in the forcefield, the charge
>>>>> optimization objective values are not nearly as good (which is to be
>>>>> expected as the degrees of freedom are reduced). However, in some cases the
>>>>> charges on the overlapping atoms can be quite different than the existing
>>>>> charge values in the the CHARMM ff if I let them optimize without
>>>>> restraints.
>>>>> Thanks for your help in advance,
>>>>> Bryan
>>>>> *Bryan Roessler | Graduate Research Assistant*
>>>>> UAB | The University of Alabama at Birmingham
>>>>> *
>>>>> <>*
>>>>> Knowledge that will change your world