ADL: Modelling water

Wim Nerinckx wim.nerinckx at ugent.be
Sat Sep 11 16:17:43 PDT 2004


Hello everyone, Dear Prof. Dr. G. Morris (congrats for the excellent 
autodock program and suite),

An "adding hydrogens to the water"-question.

What if one would first strip all waters and prepare all of the enzyme 
in the normal ADT-described way, then draw a very small box (just 
slightly bigger than "water-with-hydrogens") at the position where the 
essential water-oxygen was of the crystal structure, then auto-dock a 
water-molecule in that box, and then use the enzyme plus the 
best-docked water molecule (which now has hydrogen atoms) for 
subsequent ligand-docking? Would this not give a reasonable assumption 
of what the hydrogen positions were of the essential water molecule?

With greetings,
Wim Nerinckx, Ghent University, Belgium
(Running autodock and ADT on Apple-OSX)

On 09 Sep 2004, at 00:04, Garrett M. Morris wrote:

> Hi Smita,
>
> On Sep 8, 2004, at 7:53 am, Bhatia, Smita wrote:
>
>> Hi everyone,
>>
>> The ligand binding site in my protein has 2 water molecules that 
>> could be
>> interacting with the ligand. How can I use autodock to model these 
>> waters?
>
> You can treat the waters as part of the protein, then compute a set of 
> grid maps around the protein + water combination, but first you must 
> add their hydrogens.  Placement of the hydrogens is particularly 
> important for Thr, Ser and Tyr hydroxyls, as well as waters, of 
> course.  Some PDB structures could also form better hydrogen bond 
> networks if an Asn or Gln side chain's terminal O=C-NH2 groups are 
> flipped (presumably because the electron density map couldn't 
> unambiguously indicate which heteroatom is which).
>
> A related point to consider is the protonation state of all your 
> ionisable side chains: this will be determined by the pH and salt 
> concentrations, and you should look into pKa calculations: there is a 
> nice introduction at:
>
> 	http://enzyme.ucd.ie/Science/pKa/pKa_introduction
>
> along with a list of software 
> (http://enzyme.ucd.ie/Science/pKa/Software/).
>
>
> You will need to place the hydrogens in a reasonable place. There are 
> at least 4 options:
>
>
> (1) Use AutoDockTools to add hydrogens.
>
>
> (2) You can use InsightII's Discover, AMBER, CHARMM, GROMOS, VMD or 
> any other molecular mechanics/dynamics package to minimize the energy 
> of the system, but remember to fix the heavy atom positions and just 
> optimise the positions of the hydrogens.
>
>
> (3) Alternatively, you could use WHAT-IF's WHAT_CHECK.
>
> R.W.W. Hooft, G. Vriend, C. Sander, E.E. Abola, "Errors in protein 
> structures."  Nature, 381, 272-272 (1996).
>
> http://www.cmbi.kun.nl/gv/whatcheck/
>
>
> (4) A fourth option is you could use the PDB2PQR web server through 
> APBS portal. This can optimize the protein hydrogen network (but can 
> significantly increase computational time); and if you do this, you 
> can choose to optimize the water hydrogen network.  See:
>
> Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA. "PDB2PQR: an automated 
> pipeline for the setup, execution, and analysis of Poisson-Boltzmann 
> electrostatics calculations." Nucleic Acids Research 32 W665-W667 
> (2004).
>
> http://nbcr.sdsc.edu/pdb2pqr/index.html
>
>
>
> Remember we treat the protein with the United Atom model, which means 
> we keep polar hydrogens; the non-polar hydrogens (attached to carbons) 
> can be "merged" using AutoDockTools.  Merging means we add the partial 
> charge from the hydrogen to that of the carbon it is bonded to, then 
> delete the hydrogen.
>
> I hope this helps,
>
> Best wishes,
>
> Garrett
>
>> I also think that Autogrid will have to be changed so it would 
>> consider an
>> oxygen bound to 2 hydrogens as a potential bond acceptor, allowing for
>> correct treatment of water molecules. Can anyone suggest how to do 
>> this?
>
> AutoGrid can properly handle waters in the protein.
>
>>
>> Thanks a lot,
>>
>> Smita
>>
>>
>> **************************************
>> Smita Bhatia
>> Institute for Biological Sciences
>> National research Council
>> 100-Sussex Drive, Room # 3031
>> Ottawa, ON  K1A 0R6
>> Phone: (613)990-0855
>> Email : Smita.Bhatia at nrc-cnrc.gc.ca 
>> <mailto:Smita.Bhatia at nrc-cnrc.gc.ca>
>> **************************************
>>
>>
>> ________________________________________________
>> --- ADL: AutoDock List  --- 
>> http://www.scripps.edu/pub/olson-web/doc/autodock/ ---
> ___
> Dr Garrett M. Morris, MA, DPhil
>
> The Scripps Research Institute,       tel: (858) 784-2292
> Dept. Molecular Biology,  MB-5,       fax: (858) 784-2860
> 10550  North Torrey Pines Road,       email: garrett at scripps.edu
> La Jolla,  CA 92037-1000,  USA.       www.scripps.edu/pub/olson-web/gmm
>
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>




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