ADL: term"randomized structure"

Stefano Forli forli at scripps.edu
Fri Mar 25 14:03:56 PDT 2016


This topic is very important, and I believe it's great that such issues are discussed in 
the community.

Ideally, you would be right: if a program could perform efficient searches and unbiased 
internal randomizations, there would be no need for pre-randomizing the input externally.

Although, very likely this is not the case.
First, any conformational sampling which is not perfect will be limited by the starting 
point, even when generating the internal randomized starting point.
That's why, explicitly or under the hood, all docking programs run multiple independent 
searches.

Cases have been reported where the re-docking success rate was higher when starting from 
the experimental coordinates, even when only the geometric center of the input was 
overlapping with the solution.

Also, if for some reason (incorrect implementation, rounding errors, etc.) there is a bias 
toward toward zero values, if the internally randomized conformations are generated by 
deviating from the input state, the search will drift toward the input.

That said, randomizing the input is not a requirement for re-dockings, but it's definitely 
a good choice to simulate real-life conditions.
Crystal structures represent the ligand conformations minimized to fit the density maps, 
which depend on experimental parameters, conditions, etc., and can result in distorted 
geometries.
Ligand libraries used in virtual screening, on the other hand, have ideal coordinates, so 
could not be able to match experimental coordinates.
Testing a the re-docking of the crystallographic ligand using ideal coordinates generated 
externally can allow you to assess the chances of success of your dockings.

There are many papers on these two topics, but these are an excellent start:
http://onlinelibrary.wiley.com/doi/10.1002/prot.20497/full
http://pubs.acs.org/doi/abs/10.1021/jm8016464

Happy dockings,

S


On 03/25/2016 01:28 PM, Dinler Antunes wrote:
> Following up on this discussion on the randomized initial structure, this
> is not a requirement for redocking, right? I mean, regardless of the input
> 3D conformation of the ligand both Autodock4 and Vina will start the ligand
> using a random seed. This will be used to randomize the initial
> conformation, right? Or it will only be used to randomize rotational and
> translational degrees of freedom?
>
> BW,
>
> Dinler Antunes
>
>
> 2016-03-25 13:42 GMT-05:00 <autodock-request at scripps.edu>:
>
>> Send autodock mailing list submissions to
>>          autodock at scripps.edu
>>
>> To subscribe or unsubscribe via the World Wide Web, visit
>>          http://mgldev.scripps.edu/mailman/listinfo/autodock
>> or, via email, send a message with subject or body 'help' to
>>          autodock-request at scripps.edu
>>
>> You can reach the person managing the list at
>>          autodock-owner at scripps.edu
>>
>> When replying, please edit your Subject line so it is more specific
>> than "Re: Contents of autodock digest..."
>>
>>
>> Today's Topics:
>>
>>     1.  term"randomized structure" (maria timoshik)
>>     2. Re:  term"randomized structure" (Richard  Wood)
>>     3. Re:  term"randomized structure" (Stefano Forli)
>>     4. Re:  term"randomized structure" (Richard  Wood)
>>     5.  Question about Autodock Vina counter ions (Tye Martin)
>>     6. Re:  term"randomized structure" (Stefano Forli)
>>
>>
>> ----------------------------------------------------------------------
>>
>> Message: 1
>> Date: Thu, 24 Mar 2016 22:30:23 +0300
>> From: maria timoshik <m.timoshik at yandex.ru>
>> Subject: ADL: term"randomized structure"
>> To: "autodock at scripps.edu" <autodock at scripps.edu>
>> Message-ID: <796051458847823 at web20h.yandex.ru>
>> Content-Type: text/plain
>>
>> Hello:
>> I've heard that in a very beginning of video tutorial to Vina Dr. Oleg
>> Todd said:
>> "I'll use a randomized structure of a drug molecule".
>> What the term RANDOMIZED STRUCTURE actually mean in this context?
>> Perhaps professional physico-chemists can explain?
>>
>> with regards, Maria
>>
>>
>> ------------------------------
>>
>> Message: 2
>> Date: Fri, 25 Mar 2016 01:09:32 +0000
>> From: "Richard  Wood" <Richard.Wood at purduecal.edu>
>> Subject: Re: ADL: term"randomized structure"
>> To: "autodock at scripps.edu" <autodock at scripps.edu>
>> Message-ID:
>>          <
>> 2795F52A14F49842BB6FF8003810E47D25E1D21A at PUCEX5.staff.puc.purduecal.edu>
>>
>> Content-Type: text/plain; charset="us-ascii"
>>
>> Non-optimized?
>>
>> Richard
>>
>> ________________________________________
>> From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on
>> behalf of maria timoshik [m.timoshik at yandex.ru]
>> Sent: Thursday, March 24, 2016 2:30 PM
>> To: autodock at scripps.edu
>> Subject: ADL: term"randomized structure"
>>
>> Hello:
>> I've heard that in a very beginning of video tutorial to Vina Dr. Oleg
>> Todd said:
>> "I'll use a randomized structure of a drug molecule".
>> What the term RANDOMIZED STRUCTURE actually mean in this context?
>> Perhaps professional physico-chemists can explain?
>>
>> with regards, Maria
>> ________________________________________________
>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>
>>
>>
>> ------------------------------
>>
>> Message: 3
>> Date: Thu, 24 Mar 2016 18:17:44 -0700
>> From: Stefano Forli <forli at scripps.edu>
>> Subject: Re: ADL: term"randomized structure"
>> To: "autodock at scripps.edu" <autodock at scripps.edu>
>> Message-ID: <56F491B8.5000905 at scripps.edu>
>> Content-Type: text/plain; charset="windows-1252"; format=flowed
>>
>> Hi,
>> a general practice when testing docking programs is to prevent any kind of
>> bias in the
>> input structures that can simplify the search and artificially increase
>> re-docking success
>> rate.
>>
>> For this reason, the input structures should be randomized to be different
>> from the
>> solution, but still optimized, i.e., all bond angles and lengths must be
>> correct.
>>
>> The ideal approach would be to generate the 3D coordinates of the ligand
>> starting from
>> scratch (e.g., SMILES format) using an external software and dock that.
>>
>> Although, since during docking bond angles and lengths are not altered, it
>> is sufficient
>> to randomize the conformation of the ligand from its experimental
>> coordinates in a
>> crystallographic complex, by altering its position, orientation and all
>> the angles in
>> rotatable bonds.
>>
>>
>> S
>>
>>
>>
>> On 03/24/2016 06:09 PM, Richard  Wood wrote:
>>> Non-optimized?
>>>
>>> Richard
>>>
>>> ________________________________________
>>> From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on
>> behalf of maria timoshik [m.timoshik at yandex.ru]
>>> Sent: Thursday, March 24, 2016 2:30 PM
>>> To: autodock at scripps.edu
>>> Subject: ADL: term"randomized structure"
>>>
>>> Hello:
>>> I've heard that in a very beginning of video tutorial to Vina Dr. Oleg
>> Todd said:
>>> "I'll use a randomized structure of a drug molecule".
>>> What the term RANDOMIZED STRUCTURE actually mean in this context?
>>> Perhaps professional physico-chemists can explain?
>>>
>>> with regards, Maria
>>> ________________________________________________
>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>>
>>> ________________________________________________
>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>>
>>
>> --
>>
>>    Stefano Forli, PhD
>>
>>    Assistant Professor of Integrative
>>    Structural and Computational Biology,
>>    Molecular Graphics Laboratory
>>
>>    Dept. of Integrative Structural
>>     and Computational Biology, MB-112A
>>    The Scripps Research Institute
>>    10550  North Torrey Pines Road
>>    La Jolla,  CA 92037-1000,  USA.
>>
>>       tel: +1 (858)784-2055
>>       fax: +1 (858)784-2860
>>       email: forli at scripps.edu
>>       http://www.scripps.edu/~forli/
>>
>>
>> ------------------------------
>>
>> Message: 4
>> Date: Fri, 25 Mar 2016 13:03:07 +0000
>> From: "Richard  Wood" <Richard.Wood at purduecal.edu>
>> Subject: Re: ADL: term"randomized structure"
>> To: "autodock at scripps.edu" <autodock at scripps.edu>
>> Message-ID:
>>          <
>> 2795F52A14F49842BB6FF8003810E47D25E1D243 at PUCEX5.staff.puc.purduecal.edu>
>>
>> Content-Type: text/plain; charset="us-ascii"
>>
>> Generally, unless one uses a 2-D drawing program, most sketching programs
>> will do some kind of "quick and dirty" optimization.  So, when I said,
>> "non-optimized", that is what I was referring to.  Of course, one can also
>> do a full blown optimization and dock that as well.
>>
>> It is probably best to remove the ligand from a ligand-protein crystal
>> structure and re-dock the ligand to see if one can place it in its correct
>> position.  One can then tweak docking parameters to see if they can
>> reproduce the crystal ligand pose.  You can then calculate the RMSD between
>> your docked ligand and that of the crystal structure ligand.  If one is
>> careful, you can get an RMSD of less than 0.5.  (As an aside, I was at an
>> ACS talk a few years back, and there was a speaker from some pharma company
>> who was re-docking ligands and comparing them to the crystal.  He was proud
>> of the fact that his RMSDs were less than 2.  I told him after his talk
>> that he could do much better than that (he I was a lowly post-doc and he
>> was a "professional modeler"-I still remain far below "professional
>> modeler").)
>>
>> It's questionable how many people actually do that, however.
>>
>> Richard
>> ________________________________________
>> From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on
>> behalf of Stefano Forli [forli at scripps.edu]
>> Sent: Thursday, March 24, 2016 8:17 PM
>> To: autodock at scripps.edu
>> Subject: Re: ADL: term"randomized structure"
>>
>> Hi,
>> a general practice when testing docking programs is to prevent any kind of
>> bias in the
>> input structures that can simplify the search and artificially increase
>> re-docking success
>> rate.
>>
>> For this reason, the input structures should be randomized to be different
>> from the
>> solution, but still optimized, i.e., all bond angles and lengths must be
>> correct.
>>
>> The ideal approach would be to generate the 3D coordinates of the ligand
>> starting from
>> scratch (e.g., SMILES format) using an external software and dock that.
>>
>> Although, since during docking bond angles and lengths are not altered, it
>> is sufficient
>> to randomize the conformation of the ligand from its experimental
>> coordinates in a
>> crystallographic complex, by altering its position, orientation and all
>> the angles in
>> rotatable bonds.
>>
>>
>> S
>>
>>
>>
>> On 03/24/2016 06:09 PM, Richard  Wood wrote:
>>> Non-optimized?
>>>
>>> Richard
>>>
>>> ________________________________________
>>> From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on
>> behalf of maria timoshik [m.timoshik at yandex.ru]
>>> Sent: Thursday, March 24, 2016 2:30 PM
>>> To: autodock at scripps.edu
>>> Subject: ADL: term"randomized structure"
>>>
>>> Hello:
>>> I've heard that in a very beginning of video tutorial to Vina Dr. Oleg
>> Todd said:
>>> "I'll use a randomized structure of a drug molecule".
>>> What the term RANDOMIZED STRUCTURE actually mean in this context?
>>> Perhaps professional physico-chemists can explain?
>>>
>>> with regards, Maria
>>> ________________________________________________
>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>>
>>> ________________________________________________
>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>>
>>
>> --
>>
>>    Stefano Forli, PhD
>>
>>    Assistant Professor of Integrative
>>    Structural and Computational Biology,
>>    Molecular Graphics Laboratory
>>
>>    Dept. of Integrative Structural
>>     and Computational Biology, MB-112A
>>    The Scripps Research Institute
>>    10550  North Torrey Pines Road
>>    La Jolla,  CA 92037-1000,  USA.
>>
>>       tel: +1 (858)784-2055
>>       fax: +1 (858)784-2860
>>       email: forli at scripps.edu
>>       http://www.scripps.edu/~forli/
>> ________________________________________________
>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>
>>
>>
>> ------------------------------
>>
>> Message: 5
>> Date: Fri, 25 Mar 2016 17:09:15 +0000
>> From: Tye Martin <tmarti16 at unm.edu>
>> Subject: ADL: Question about Autodock Vina counter ions
>> To: "autodock at scripps.edu" <autodock at scripps.edu>
>> Message-ID:
>>          <
>> CY1PR0701MB1678C3DE890B83A89BC57207C6830 at CY1PR0701MB1678.namprd07.prod.outlook.com
>>>
>>
>> Content-Type: text/plain; charset="iso-8859-1"
>>
>> Hello,
>>
>> I was wondering if Vina uses any kind of counter ions during the
>> simulation process? I study charged ligand-protein systems and use counter
>> ions during molecular dynamics simulations, so I was just curious if
>> docking does something similar by default.
>>
>> Thank you.
>>
>>
>>
>> ------------------------------
>>
>> Message: 6
>> Date: Fri, 25 Mar 2016 11:42:51 -0700
>> From: Stefano Forli <forli at scripps.edu>
>> Subject: Re: ADL: term"randomized structure"
>> To: "autodock at scripps.edu" <autodock at scripps.edu>
>> Message-ID: <56F586AB.5050307 at scripps.edu>
>> Content-Type: text/plain; charset="windows-1252"; format=flowed
>>
>> Hi Richard,
>> just to clarify, if you create your molecule from scratch (e.g., you
>> sketch it from a 2D
>> programs like ChemDraw) you want to carefully prepare the 3D coordinates,
>> so you *must* do
>> a complete minimization.
>>
>> In fact, pretty much every docking software (including AutoDock) do not
>> alter bond angles
>> and lengths during the calculation, so if your structure is distorted or
>> not optimal, it
>> will lead to poor/wrong results.
>> Several papers showed redocking ligand structures generated from SMILES
>> can reduce docking
>> accuracy by >20%.
>>
>> About the RMSD cutoff, 2.0 A is widely accepted as the standard for
>> evaluating docking
>> performance, even though there's strong agreement on RMSD itself being a
>> poor metric for
>> docking accuracy.
>> Alternatives get constantly proposed, but despite its limitations, within
>> 2.0 A range you
>> can assume that most of the known essential interactions with the target
>> have been
>> established.
>>
>> Best,
>>
>> S
>>
>> On 03/25/2016 06:03 AM, Richard  Wood wrote:
>>> Generally, unless one uses a 2-D drawing program, most sketching
>> programs will do some kind of "quick and dirty" optimization.  So, when I
>> said, "non-optimized", that is what I was referring to.  Of course, one can
>> also do a full blown optimization and dock that as well.
>>>
>>> It is probably best to remove the ligand from a ligand-protein crystal
>> structure and re-dock the ligand to see if one can place it in its correct
>> position.  One can then tweak docking parameters to see if they can
>> reproduce the crystal ligand pose.  You can then calculate the RMSD between
>> your docked ligand and that of the crystal structure ligand.  If one is
>> careful, you can get an RMSD of less than 0.5.  (As an aside, I was at an
>> ACS talk a few years back, and there was a speaker from some pharma company
>> who was re-docking ligands and comparing them to the crystal.  He was proud
>> of the fact that his RMSDs were less than 2.  I told him after his talk
>> that he could do much better than that (he I was a lowly post-doc and he
>> was a "professional modeler"-I still remain far below "professional
>> modeler").)
>>>
>>> It's questionable how many people actually do that, however.
>>>
>>> Richard
>>> ________________________________________
>>> From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on
>> behalf of Stefano Forli [forli at scripps.edu]
>>> Sent: Thursday, March 24, 2016 8:17 PM
>>> To: autodock at scripps.edu
>>> Subject: Re: ADL: term"randomized structure"
>>>
>>> Hi,
>>> a general practice when testing docking programs is to prevent any kind
>> of bias in the
>>> input structures that can simplify the search and artificially increase
>> re-docking success
>>> rate.
>>>
>>> For this reason, the input structures should be randomized to be
>> different from the
>>> solution, but still optimized, i.e., all bond angles and lengths must be
>> correct.
>>>
>>> The ideal approach would be to generate the 3D coordinates of the ligand
>> starting from
>>> scratch (e.g., SMILES format) using an external software and dock that.
>>>
>>> Although, since during docking bond angles and lengths are not altered,
>> it is sufficient
>>> to randomize the conformation of the ligand from its experimental
>> coordinates in a
>>> crystallographic complex, by altering its position, orientation and all
>> the angles in
>>> rotatable bonds.
>>>
>>>
>>> S
>>>
>>>
>>>
>>> On 03/24/2016 06:09 PM, Richard  Wood wrote:
>>>> Non-optimized?
>>>>
>>>> Richard
>>>>
>>>> ________________________________________
>>>> From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on
>> behalf of maria timoshik [m.timoshik at yandex.ru]
>>>> Sent: Thursday, March 24, 2016 2:30 PM
>>>> To: autodock at scripps.edu
>>>> Subject: ADL: term"randomized structure"
>>>>
>>>> Hello:
>>>> I've heard that in a very beginning of video tutorial to Vina Dr. Oleg
>> Todd said:
>>>> "I'll use a randomized structure of a drug molecule".
>>>> What the term RANDOMIZED STRUCTURE actually mean in this context?
>>>> Perhaps professional physico-chemists can explain?
>>>>
>>>> with regards, Maria
>>>> ________________________________________________
>>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list
>> ---
>>>>
>>>> ________________________________________________
>>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list
>> ---
>>>>
>>>
>>> --
>>>
>>>     Stefano Forli, PhD
>>>
>>>     Assistant Professor of Integrative
>>>     Structural and Computational Biology,
>>>     Molecular Graphics Laboratory
>>>
>>>     Dept. of Integrative Structural
>>>      and Computational Biology, MB-112A
>>>     The Scripps Research Institute
>>>     10550  North Torrey Pines Road
>>>     La Jolla,  CA 92037-1000,  USA.
>>>
>>>        tel: +1 (858)784-2055
>>>        fax: +1 (858)784-2860
>>>        email: forli at scripps.edu
>>>        http://www.scripps.edu/~forli/
>>> ________________________________________________
>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>>
>>> ________________________________________________
>>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>>>
>>
>> --
>>
>>    Stefano Forli, PhD
>>
>>    Assistant Professor of Integrative
>>    Structural and Computational Biology,
>>    Molecular Graphics Laboratory
>>
>>    Dept. of Integrative Structural
>>     and Computational Biology, MB-112A
>>    The Scripps Research Institute
>>    10550  North Torrey Pines Road
>>    La Jolla,  CA 92037-1000,  USA.
>>
>>       tel: +1 (858)784-2055
>>       fax: +1 (858)784-2860
>>       email: forli at scripps.edu
>>       http://www.scripps.edu/~forli/
>>
>>
>> ------------------------------
>>
>> ________________________________________________
>> --- ADL: AutoDock List  ---
>> http://www.scripps.edu/pub/olson-web/doc/autodock/ ---
>>
>> End of autodock Digest, Vol 139, Issue 14
>> *****************************************
>>
>
>
>
> --
> Dinler Amaral Antunes
> ________________________________________________
> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>

-- 

  Stefano Forli, PhD

  Assistant Professor of Integrative
  Structural and Computational Biology,
  Molecular Graphics Laboratory

  Dept. of Integrative Structural
   and Computational Biology, MB-112A
  The Scripps Research Institute
  10550  North Torrey Pines Road
  La Jolla,  CA 92037-1000,  USA.

     tel: +1 (858)784-2055
     fax: +1 (858)784-2860
     email: forli at scripps.edu
     http://www.scripps.edu/~forli/


More information about the autodock mailing list