[gmx-users] [gmx-user] RMSD analysis of protein-ligand complex

[Justin Lemkul]

On 12/26/19 6:11 PM, Quin K wrote:
> Okay thank you!
> *What exactly should I do to fix the topology high penalty?*
> Do a DFT optimization again for the molecule and do the parametrization ?
> Is there a guideline to follow?

The CGenFF paper (JCC 2010) is a how-to for the entire force field and 
how to be sure you're compatible with the parent CHARMM force field.

There are also separate tutorial materials here: 
http://mackerell.umaryland.edu/~kenno/cgenff/download.php#tutor

-Justin

> On Thu, Dec 26, 2019 at 10:07 PM Justin Lemkul <jalemkul at vt.edu> wrote:
>
>> On Thu, Dec 26, 2019 at 9:41 AM Quin K <profiles.ke at gmail.com> wrote:
>>
>>> Thank you!
>>> I noted that there are two options called
>>>   Guess bond orders from connectivity
>>>   Include parameters that are already in CGenFF
>>> In the parachem website.
>>> Would checking these specially the second one would fix some of these
>>> problems?
>>
>> No. Work with the topology you have. The second option also has nothing to
>> do with parameter assignment and will lead to duplicate parameter errors
>> later.
>>
>> -Justin
>>
>>
>>> I have not used these options.
>>>
>>> Regards!
>>>
>>> On Thu, Dec 26, 2019 at 6:54 PM Justin Lemkul <jalemkul at vt.edu> wrote:
>>>
>>>>
>>>> On 12/26/19 9:05 AM, Quin K wrote:
>>>>> Thank you!
>>>>> This is the output I got from parachem.
>>>>>
>> https://docs.google.com/document/d/180rWUj4XE-_OFBCVPsJajohNRKUYIClcP_V3cOer5qw/view
>>>>> Can this be used as it is?
>>>>>
>>>>> I used it as it is and did not validate or optimized further, could
>>> that
>>>> be
>>>>> the reason why ligand got detached from binding site during MD
>>>> simulation?
>>>>
>>>> Possibly. The charge and dihedral penalties are not low enough to be
>>>> considered sufficient without explicit validation using QM water
>>>> interaction energy and a 1-D potential energy surface around the
>>>> (potentially) problematic dihedral. It may be that the topology is
>> fine,
>>>> but as the header says, penalties between 10-50 cannot be trusted
>>>> without proving the parameters are OK.
>>>>
>>>> -Justin
>>>>
>>>>> Thanks in advance!
>>>>> Regards
>>>>> Q
>>>>>
>>>>> On Wed, Dec 18, 2019 at 1:23 PM Justin Lemkul <jalemkul at vt.edu>
>> wrote:
>>>>>> On 12/18/19 6:40 AM, Quin K wrote:
>>>>>>> I generated ligand topology using parachem website, I didn't do any
>>>>>>> adjustments after, just used it as it is.
>>>>>> What do the penalty scores tell you about the quality of the
>>> parameters?
>>>>>> -Justin
>>>>>>
>>>>>>> On Tue, 17 Dec 2019, 1:11 pm Justin Lemkul, <jalemkul at vt.edu>
>> wrote:
>>>>>>>> On 12/15/19 1:18 PM, Quin K wrote:
>>>>>>>>> Hi
>>>>>>>>> Thank you!!!
>>>>>>>>>
>>>>>>>>> Let's say during restraining of ligand, if I increased  the -fc
>>> value
>>>>>> to
>>>>>>>>> 10000 (i had 1000) or higher and equilibrated it for longer time
>>>> like 1
>>>>>>>> or
>>>>>>>>> 2 ns (I had 100ps), would it help?
>>>>>>>> Possibly.
>>>>>>>>
>>>>>>>>> Also would  restraining the protein and ligand independently
>> help?
>>>>>>>>> Or is generating a better ligand topology the only way to solve
>>> this
>>>>>>>> issue?
>>>>>>>>
>>>>>>>> It depends on how you validated the ligand topology. Do you have
>>>>>>>> evidence that it is of sufficiently high quality?
>>>>>>>>
>>>>>>>> -Justin
>>>>>>>>
>>>>>>>>> Thanks in advance.
>>>>>>>>> Regards
>>>>>>>>>
>>>>>>>>> On Sun, Dec 15, 2019 at 11:07 PM Justin Lemkul <jalemkul at vt.edu>
>>>>>> wrote:
>>>>>>>>>> On 12/15/19 11:47 AM, Quin K wrote:
>>>>>>>>>>> Hi All,
>>>>>>>>>>>
>>>>>>>>>>> Further to following email, i just noted that the ligand has
>>>> detached
>>>>>>>>>> from
>>>>>>>>>>> binding site.
>>>>>>>>>>> Is there a way to prevent this from happening?
>>>>>>>>>>> It happened to me once before with the same complex.
>>>>>>>>>> If the ligand is dissociating on a time scale that it shouldn't
>>>> (e.g.
>>>>>>>>>> you expect it should stay bound), that suggests the ligand
>>> topology
>>>> is
>>>>>>>>>> insufficiently accurate, arising from interactions with the
>>> protein
>>>>>> that
>>>>>>>>>> are too weak and/or interactions with water that are too strong.
>>>>>>>>>>
>>>>>>>>>>> Doesn't boundary conditions prevent ligand from detaching from
>>>>>> binding
>>>>>>>>>> site
>>>>>>>>>>> in protein during MD simulation?
>>>>>>>>>> No, PBC does not do this. A periodic system contains copies of
>>>>>> whatever
>>>>>>>>>> is happening in the central image.
>>>>>>>>>>
>>>>>>>>>> -Justin
>>>>>>>>>>
>>>>>>>>>> --
>>>>>>>>>> ==================================================
>>>>>>>>>>
>>>>>>>>>> Justin A. Lemkul, Ph.D.
>>>>>>>>>> Assistant Professor
>>>>>>>>>> Office: 301 Fralin Hall
>>>>>>>>>> Lab: 303 Engel Hall
>>>>>>>>>>
>>>>>>>>>> Virginia Tech Department of Biochemistry
>>>>>>>>>> 340 West Campus Dr.
>>>>>>>>>> Blacksburg, VA 24061
>>>>>>>>>>
>>>>>>>>>> jalemkul at vt.edu | (540) 231-3129
>>>>>>>>>> http://www.thelemkullab.com
>>>>>>>>>>
>>>>>>>>>> ==================================================
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>>>>>>>> --
>>>>>>>> ==================================================
>>>>>>>>
>>>>>>>> Justin A. Lemkul, Ph.D.
>>>>>>>> Assistant Professor
>>>>>>>> Office: 301 Fralin Hall
>>>>>>>> Lab: 303 Engel Hall
>>>>>>>>
>>>>>>>> Virginia Tech Department of Biochemistry
>>>>>>>> 340 West Campus Dr.
>>>>>>>> Blacksburg, VA 24061
>>>>>>>>
>>>>>>>> jalemkul at vt.edu | (540) 231-3129
>>>>>>>> http://www.thelemkullab.com
>>>>>>>>
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>>>>>> --
>>>>>> ==================================================
>>>>>>
>>>>>> Justin A. Lemkul, Ph.D.
>>>>>> Assistant Professor
>>>>>> Office: 301 Fralin Hall
>>>>>> Lab: 303 Engel Hall
>>>>>>
>>>>>> Virginia Tech Department of Biochemistry
>>>>>> 340 West Campus Dr.
>>>>>> Blacksburg, VA 24061
>>>>>>
>>>>>> jalemkul at vt.edu | (540) 231-3129
>>>>>> http://www.thelemkullab.com
>>>>>>
>>>>>> ==================================================
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>>>> --
>>>> ==================================================
>>>>
>>>> Justin A. Lemkul, Ph.D.
>>>> Assistant Professor
>>>> Office: 301 Fralin Hall
>>>> Lab: 303 Engel Hall
>>>>
>>>> Virginia Tech Department of Biochemistry
>>>> 340 West Campus Dr.
>>>> Blacksburg, VA 24061
>>>>
>>>> jalemkul at vt.edu | (540) 231-3129
>>>> http://www.thelemkullab.com
>>>>
>>>> ==================================================
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>> --
>>
>> ==========================================
>>
>> Justin A. Lemkul, Ph.D.
>>
>> Assistant Professor
>>
>> Office: 301 Fralin Hall
>> Lab: 303 Engel Hall
>>
>> Virginia Tech Department of Biochemistry
>> 340 West Campus Dr.
>> Blacksburg, VA 24061
>>
>> jalemkul at vt.edu | (540) 231-3129
>> http://www.thelemkullab.com
>>
>>
>> ==========================================
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-- 
==================================================

Justin A. Lemkul, Ph.D.
Assistant Professor
Office: 301 Fralin Hall
Lab: 303 Engel Hall

Virginia Tech Department of Biochemistry
340 West Campus Dr.
Blacksburg, VA 24061

jalemkul at vt.edu | (540) 231-3129
http://www.thelemkullab.com

==================================================