[Dock-fans] Unbiased docking

[Scott Brozell]

Hi,

On Sat, 27 Oct 2007, Francesco Pietra wrote:

> --- Scott Brozell <sbrozell at scripps.edu> wrote:
> 
> > On Sun, 21 Oct 2007, Francesco Pietra wrote:
> > 
> > > Based on the suggestions below, I have followed the layout and settings of
> > the
> > > Dock6.1-web-page tutorials for my model pore protein (3400 heavy atoms,
> > noH, no
> > > solvent added) and 150-atoms neutral, lipidic ligand (bearing all
> > hydrogens),
> > > using the minimum energy conformation of the latter from Amber9 simulated
> > > annealing in vacuum.
> > > 
> > > sphgen failed, while sphgen_cpp built re.ms and rec.sph in a few minutes,
> > > 118807 surface points in 91 clusters. I was surprised to see roughly the
> > same
> > > sphere distribution for clusters # 1, 2, and 91. Hope that sounds correct.
> > I
> > > did not examine other clusters, and all was done very roughly at the open
> > eye.
> > > 
> > > Grid OK in ca 1h and half.
> > > 
> > > Rigid docking completed in 5 min wall time, showing the elongated ligand
> > (made
> > > of annealed rings) inside the cone, with the head out. Grid score -52.3.
> > > 
> > > Flex docking (cpu time ca 3h; anchors 1; orientations 500, conformations
> > 115,
> > > grid score -69.2, vdw -67.2, es -2). The arrangement of the ligand within
> > the
> > > pore was roughly the same as for rigid  docking, through the head of the
> > ligand
> > > was docked differently.
> > > 
> > > I did not carry out any docking with higher-energy conformers of the
> > ligand.
> > 
> > 
> > I do not notice any red flags in the above, but I do not have any
> > experience with pore proteins.
> 
> As I told in the thread on "TER removed", red flags came with amber_score in
> DOCK6.1. While the files associated with the ligand were OK, the inpcrd and
> prmtop files were desolatingly empty. The error log suggested some of the steps
> about which I told on the "TER removed" thread. Coming the first time at
> docking, and with a pore protein model, which was also my first creation of
> pores, I didn't expect any rapid success. It will be an exciting experience if
> I finally succeed. I am most curios if the docking I observed is specific of
> that molecule (I know experimentally that it interacts with the pore protein).
> Once Amber simulations will also succeed, I'll try with other molecules of that
> family which do not affect the pore protein. Then, should the lipid bilayer be
> present? The ligands are strictly lipidic.


I do not have any experience simulating lipid bilayers.
Some obvious points are
how close to the lipid bilayer are the active site(s) ?
how does the lipid bilayer affect the pore protein conformation ?
is the pore protein stable (in MD) without the lipid bilayer ?

Scott

> > > This long story because it is the first time I am at docking outside
> > tutorials,
> > > to hopefully get suggestions as to go on. I could either carry out amber
> > score,
> > > and the relevant tutorial I have found outside the dock web page is clear
> > > enough. Is that what Scott had in mind when he kindly suggested "go to
> > Amber
> > > after docking, and with the MD results back to Dock" or should I rather
> > skip
> > > amber scoring and go directly to Amber 9 to carry out a regular MD, may be
> > with
> > > the pore model inside POPC? If so, which is the shortest way to use my
> > above
> > > results from DOCK to set up the Amber 9 MD? (I mean, how to save the pore
> > > protein plus the ligand so that Amber 9 can work; I am familiar with prmtop
> > and
> > > inprc file, while I read that Amber 9 can't import mol2 files with more
> > than
> > > one residue; if I save protein+ligand as pdb, how to get parameters for the
> > > ligand? Or, if I save the protein and ligand separately do they conserve
> > their
> > > respective positions?.
> > 
> > 
> > My recollection is that I suggested DOCK for docking and Amber for MD.
> > There are a number of ways to go from docking results to MD.
> > If you rescore with Amber Score in DOCK then the Amber score preparation
> > and the DOCK outputs contain Amber readable prmtop and inpcrd files.
> > See
> > http://dock.compbio.ucsf.edu/DOCK_6/dock6_manual.htm#AMBERScore
> > for a description of the output files.  Also running DOCK with the
> > verbose flag, -v, may help to see what's happening under the hood.
> > (Currently the verbose output follows the normal DOCK output
> > when -o is used; so first try -v without -o.)
> > 
> > Scott
> > 
> > > --- Scott Brozell <sbrozell at scripps.edu> wrote:
> > > 
> > > > Hi,
> > > > 
> > > > On Fri, 28 Sep 2007, Francesco Pietra wrote:
> > > > 
> > > > > Although not yet ready with DOCK6.1 installation, inspection of
> > tutorials
> > > > > prompts a couple of questions that may help planning.
> > > > >
> > > > > What I want to do at the moment is verifying if there is docking at all
> > > > between
> > > > > a family of natural products and a complicated protein. Not in a
> > bilayer
> > > > for
> > > > > the moment.
> > > > >
> > > > > I have already carried out a conformational search for my natural
> > products
> > > > by
> > > > > simulated annealing with an algorithm that calls Amber9. Parameter and
> > > > > coordinate files for Amber9 were built with Antechamber/Divcon (ie
> > AM1).
> > > > >
> > > > > The tutorial on DOCK web site starts from a protein-ligand complex, ie
> > from
> > > > a
> > > > > definite receptor site in the protein. Is any graphical or alphanumeric
> > > > > tutorial for the unbiased docking I am aimed at?
> > > > 
> > > > Not that I am aware of.
> > > > There is a lot of flexibility in binding sites selection;
> > > > see step 3 of
> > > >
> > >
> >
> http://dock.compbio.ucsf.edu/DOCK_6/tutorials/sphere_generation/generating_spheres.htm
> > > > If your complicated protein is big then that may put a practical limit
> > > > on the size of your grid; one approach would be to divide and conquer
> > > > the big protein binding sites into subsets that would be processed
> > > > separately.
> > > > Perhaps others have comments ?
> > > > 
> > > > > DOCK6.1 is being compiled on a parallel amd64 machine (Debian Linux
> > amd64
> > > > with
> > > > > 4GB RAM per cpu, ie a machine better suited for ab initio calculations
> > than
> > > > > classical MD), where also Amber9 is installed. Although the X system
> > exists
> > > > (in
> > > > > fact, xleap requires it) and even Gnome could be called, the machine is
> > > > > normally used with X killed. I manage anything graphical for Amber9 (to
> > the
> > > > > exception of xleap) on a single-Athlon desktop (Debian Linux i386
> > etch).
> > > > The
> > > > > two machines are scp linked, which is the way I exchange files between
> > the
> > > > two
> > > > > machines.
> > > > >
> > > > > At 32bit I (1) prepare pdb files for "small molecules" with a MM
> > package;
> > > > (2)
> > > > > examine everything graphical with VMD.
> > > > >
> > > > > On these basis, where to install Chimera for DOCK? I noticed that
> > Chimera
> > > > calls
> > > > > both Dock Prep and Antechamber.
> > > > 
> > > > 
> > > > Installing Chimera on the same machine as VMD seems reasonable.
> > > > Any textual input and output files can be communicated between the
> > machines.
> > > > 
> > > > > Similarly, where to install dms for DOCK?
> > > > 
> > > > dms is small.  I install it in my dock directory.
> > > > 
> > > > 
> > > > > I understand that these are generic question, normally not for mailing
> > > > lists.
> > > > > Though, a couple of suggestions would greatly help me (an organic
> > chemist,
> > > > just
> > > > > now beginning to touch the area of the biochemist) in the high
> > complexity
> > > > of
> > > > > the docking affairs.
> > > > 
> > > > 
> > > > This is the best place for all questions.
> > > > 
> > > > Scott
> > 
> > 
> > 
> > 
> 
> 
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