AMBER Archive (2008)

Subject: Re: AMBER: Problems simulating a protein-ligand complex

From: Adrian Roitberg (roitberg_at_qtp.ufl.edu)
Date: Sat Jun 07 2008 - 07:36:21 CDT

Sasha,
One more suggestion, truly important.

If you are using either Andersen or Langevin thermostats, CHANGE the
random seed for each of your short runs.

Basically, all you mdins must be modified to have a different ig value.
Cheers
a.

Sasha Buzko wrote:
> Thanks, Ross.
> Will try it on Monday.
>
> Cheers
>
> Sasha
>
>
> Ross Walker wrote:
>>
>> Hi Sasha,
>>
>>
>>
>> Okay, that is just weird... I suspect there is a parameter that is
>> making something collapse onto another atom, perhaps a dodgy VDW
>> radii. I assume all the test cases pass without problems.
>>
>>
>>
>> Something to try.
>>
>>
>>
>> Set Maxcyc=200, ncyc=200, ntpr=1 and ntwr=-1
>>
>>
>>
>> This way you will be able to see every step in the mdout file. You
>> will also get a restart file for every step. In this way you can look
>> at the structure immediately before it turns to NaNs and see how it
>> differs from th initial structure. This will hopefully identify which
>> atom / region is causing the problems.
>>
>>
>>
>> All the best
>>
>> Ross
>>
>>
>>
>> *From:* owner-amber_at_scripps.edu [mailto:owner-amber_at_scripps.edu] *On
>> Behalf Of *Sasha Buzko
>> *Sent:* Friday, June 06, 2008 4:40 PM
>> *To:* amber_at_scripps.edu
>> *Subject:* RE: AMBER: Problems simulating a protein-ligand complex
>>
>>
>>
>> Ross,
>> The output is below. Thanks
>>
>>
>> -------------------------------------------------------
>> Amber 9 SANDER 2006
>> -------------------------------------------------------
>>
>> | PMEMD implementation of SANDER, Release 9
>>
>> | Run on 06/06/2008 at 16:09:26
>>
>> [-O]verwriting output
>>
>> File Assignments:
>> | MDIN:
>> min.in
>> | MDOUT:
>> complex_min.out |
>> INPCRD:
>> complex.inpcrd
>> | PARM:
>> complex.prmtop |
>> RESTRT:
>> complex_min.rst
>> | REFC:
>> refc
>> | MDVEL:
>> mdvel
>> | MDEN:
>> mden
>> | MDCRD:
>> mdcrd |
>> MDINFO:
>> mdinfo
>> |LOGFILE:
>> logfile
>>
>> Here is the input file:
>>
>> Initial minimisation of our
>> complex
>> &cntrl
>>
>> imin=1, maxcyc=1000,
>> ncyc=400, cut=20,
>> ntb=0, igb=1,
>> /
>>
>>
>>
>>
>> | Conditional Compilation Defines Used:
>> | DIRFRC_COMTRANS
>> | DIRFRC_EFS
>> | DIRFRC_NOVEC
>> | MPI
>> | SLOW_NONBLOCKING_MPI
>> | PUBFFT
>> | FFTLOADBAL_2PROC
>> | MKL
>>
>> | New format PARM file being parsed.
>> | Version = 1.000 Date = 06/06/08 Time = 16:01:47
>> | Duplicated 0 dihedrals
>>
>> | Duplicated 0 dihedrals
>>
>> --------------------------------------------------------------------------------
>>
>> 1. RESOURCE USE:
>> --------------------------------------------------------------------------------
>>
>>
>> NATOM = 2694 NTYPES = 17 NBONH = 1329 MBONA = 1388
>> NTHETH = 3017 MTHETA = 1881 NPHIH = 5748 MPHIA = 4591
>> NHPARM = 0 NPARM = 0 NNB = 14815 NRES = 168
>> NBONA = 1388 NTHETA = 1881 NPHIA = 4591 NUMBND = 59
>> NUMANG = 119 NPTRA = 52 NATYP = 43 NPHB = 0
>> IFBOX = 0 NMXRS = 46 IFCAP = 0 NEXTRA = 0
>> NCOPY = 0
>>
>> Implicit solvent radii are modified Bondi radii
>> (mbondi)
>> --------------------------------------------------------------------------------
>>
>> 2. CONTROL DATA FOR THE RUN
>> --------------------------------------------------------------------------------
>>
>>
>>
>>
>>
>> General flags:
>> imin = 1, nmropt = 0
>>
>> Nature and format of input:
>> ntx = 1, irest = 0, ntrx = 1
>>
>> Nature and format of output:
>> ntxo = 1, ntpr = 50, ntrx = 1, ntwr
>> = 500
>> iwrap = 0, ntwx = 0, ntwv = 0, ntwe
>> = 0
>> ioutfm = 0, ntwprt = 0, idecomp = 0,
>> rbornstat= 0
>>
>> Potential function:
>> ntf = 1, ntb = 0, igb = 1, nsnb
>> = 25
>> ipol = 0, gbsa = 0, iesp = 0
>> dielc = 1.00000, cut = 20.00000, intdiel = 1.00000
>> saltcon = 0.00000, offset = 0.09000, gbalpha= 1.00000
>> gbbeta = 0.00000, gbgamma = 0.00000, surften = 0.00500
>> rdt = 0.00000, rgbmax = 25.00000
>> alpb = 0
>> scnb = 2.00000, scee = 1.20000
>>
>> Frozen or restrained atoms:
>> ibelly = 0, ntr = 0
>>
>> Energy minimization:
>> maxcyc = 1000, ncyc = 400, ntmin = 1
>> dx0 = 0.01000, drms = 0.00010
>>
>> --------------------------------------------------------------------------------
>>
>> 3. ATOMIC COORDINATES AND VELOCITIES
>> --------------------------------------------------------------------------------
>>
>>
>>
>>
>> begin time read from input coords = 0.000 ps
>>
>> Number of triangulated 3-point waters found: 0
>> | Dynamic Memory, Types Used:
>> | Reals 81794
>> | Integers 252050
>>
>> | Running AMBER/MPI version on 2 nodes
>>
>>
>> --------------------------------------------------------------------------------
>>
>> 4. RESULTS
>> --------------------------------------------------------------------------------
>>
>>
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 1 -6.8120E+03 1.3612E+01 2.1864E+02 H42 2691
>>
>> BOND = 361.7247 ANGLE = 397.1223 DIHED =
>> 1628.3352
>> VDWAALS = -1261.3284 EEL = -11082.6784 EGB =
>> -2549.3611
>> 1-4 VDW = 700.0442 1-4 EEL = 4994.1524 RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 50 -7.7370E+03 8.4612E-01 1.9291E+01 PB 2656
>>
>> BOND = 86.0923 ANGLE = 347.5428 DIHED =
>> 1607.9732
>> VDWAALS = -1480.4067 EEL = -11036.0858 EGB =
>> -2588.3621
>> 1-4 VDW = 595.7157 1-4 EEL = 4730.5444 RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 100 -7.8256E+03 6.4938E-01 1.8211E+01 CG 1860
>>
>> BOND = 95.2522 ANGLE = 376.9760 DIHED =
>> 1605.2109
>> VDWAALS = -1506.3884 EEL = -11062.2867 EGB =
>> -2567.6875
>> 1-4 VDW = 572.7459 1-4 EEL = 4660.5666 RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 150 NaN NaN 0.0000E+00 N 1
>>
>> BOND = NaN ANGLE = NaN DIHED =
>> 0.0000
>> VDWAALS = NaN EEL = NaN EGB
>> = NaN
>> 1-4 VDW = NaN 1-4 EEL = NaN RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 200 NaN NaN 0.0000E+00 N 1
>>
>> BOND = NaN ANGLE = NaN DIHED =
>> 0.0000
>> VDWAALS = NaN EEL = NaN EGB
>> = NaN
>> 1-4 VDW = NaN 1-4 EEL = NaN RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 250 NaN NaN 0.0000E+00 N 1
>>
>> BOND = NaN ANGLE = NaN DIHED =
>> 0.0000
>> VDWAALS = NaN EEL = NaN EGB
>> = NaN
>> 1-4 VDW = NaN 1-4 EEL = NaN RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 300 NaN NaN 0.0000E+00 N 1
>>
>> BOND = NaN ANGLE = NaN DIHED =
>> 0.0000
>> VDWAALS = NaN EEL = NaN EGB
>> = NaN
>> 1-4 VDW = NaN 1-4 EEL = NaN RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 350 NaN NaN 0.0000E+00 N 1
>>
>> BOND = NaN ANGLE = NaN DIHED =
>> 0.0000
>> VDWAALS = NaN EEL = NaN EGB
>> = NaN
>> 1-4 VDW = NaN 1-4 EEL = NaN RESTRAINT =
>> 0.0000
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 400 NaN NaN 0.0000E+00 N 1
>>
>> BOND = NaN ANGLE = NaN DIHED =
>> 0.0000
>> VDWAALS = NaN EEL = NaN EGB
>> = NaN
>> 1-4 VDW = NaN 1-4 EEL = NaN RESTRAINT =
>> 0.0000
>>
>> .... RESTARTED DUE TO LINMIN FAILURE ...
>>
>> .... RESTARTED DUE TO LINMIN FAILURE ...
>>
>> .... RESTARTED DUE TO LINMIN FAILURE ...
>>
>> .... RESTARTED DUE TO LINMIN FAILURE ...
>>
>> .... RESTARTED DUE TO LINMIN FAILURE ...
>>
>>
>> FINAL RESULTS
>>
>>
>>
>> NSTEP ENERGY RMS GMAX NAME NUMBER
>> 421 NaN NaN 0.0000E+00 N 1
>>
>> BOND = NaN ANGLE = NaN DIHED =
>> 0.0000
>> VDWAALS = NaN EEL = NaN EGB
>> = NaN
>> 1-4 VDW = NaN 1-4 EEL = NaN RESTRAINT =
>> 0.0000
>>
>> ***** REPEATED LINMIN FAILURE *****
>> --------------------------------------------------------------------------------
>>
>> 5. TIMINGS
>> --------------------------------------------------------------------------------
>>
>>
>> | NonSetup CPU Time in Major Routines, Average for All Tasks:
>> |
>> | Routine Sec %
>> | ------------------------------
>> | DataDistrib 0.68 0.14
>> | Nonbond 493.96 99.54
>> | Bond 0.02 0.00
>> | Angle 0.17 0.03
>> | Dihedral 1.39 0.28
>> | Shake 0.00 0.00
>> | Other 0.04 0.01
>> | ------------------------------
>> | Total 496.26
>>
>> | Generalized Born CPU Time, Average for All Tasks:
>> |
>> | Routine Sec %
>> | ------------------------------------
>> | Radii Calc 37.90 7.64
>> | Diagonal Calc 263.50 53.10
>> | Off Diagonal Calc 192.32 38.75
>> | Radii Distrib 0.24 0.05
>> | ---------------------------------
>> | Total 493.96 99.54
>>
>> | Master Setup CPU time: 0.03 seconds
>> | Master NonSetup CPU time: 496.69 seconds
>> | Master Total CPU time: 496.72 seconds 0.14 hours
>>
>> | Master Setup wall time: 0 seconds
>> | Master NonSetup wall time: 261 seconds
>> | Master Total wall time: 261 seconds 0.07 hours
>>
>>
>> On Fri, 2008-06-06 at 16:34 -0700, Ross Walker wrote:
>>
>> Hi Sasha,
>>
>>
>>
>> Can you post the output file from the minimization? You probably have
>> two atoms sitting on top of each other or very close.
>>
>>
>>
>> All the best
>>
>> Ross
>>
>>
>>
>> *From:*owner-amber_at_scripps.edu [mailto:owner-amber_at_scripps.edu]
>> *On Behalf Of *Sasha Buzko
>> *Sent:* Friday, June 06, 2008 4:13 PM
>> *To:* amber_at_scripps.edu
>> *Subject:* RE: AMBER: Problems simulating a protein-ligand complex
>>
>>
>> Hi Ross,
>> thank you for the detailed instructions (although I'm trying to
>> use GB and avoid having to add explicit solvent).
>>
>> I did get a complex with the correct position of the ligand (used
>> Sirius to check the prmtop/inpcrd). But at the stage of
>> minimization I run into NaN values for all energies after about
>> 100 steps (in the minimization out file). Not sure whether it's
>> missing parameters or something else.. frcmod file had the following:
>>
>> IMPROPER
>> c3-cc-na-cc 1.1 180.0 2.0 Using
>> default value
>> h5-na-cc-nd 1.1 180.0 2.0 Using
>> default value
>> c -cc-cd-nd 1.1 180.0 2.0 Using
>> default value
>> cd-nc-c -o 10.5 180.0 2.0
>> General improper torsional angle (2 general atom types)
>> na-nc-cd-nh 1.1 180.0 2.0 Using
>> default value
>> cd-hn-nh-hn 1.1 180.0 2.0 Using
>> default value
>> cc-cd-na-hn 1.1 180.0 2.0
>> General improper torsional angle (2 general atom types)
>> cd-na-cc-na 1.1 180.0 2.0 Using
>> default value
>>
>>
>> But again, I'm not sure what could cause the issue with NaN
>> values. Since the ligand is a triphosphate, I set its charge to -3
>> (using -nc -3 flag for antechamber). In any event, I'm a bit low
>> on possible causes..
>> Can you think of anything in this regard?
>>
>> Thanks again
>>
>> Sasha
>>
>>
>> On Fri, 2008-06-06 at 15:55 -0700, Ross Walker wrote:
>>
>>
>>
>> Hi Sasha,
>>
>>
>> I would do something along the lines of the following:
>>
>>
>> 1) open protein pdb in a text editor and remove the END (at the
>> end) and just make sure there is a ter card there. Also remove any
>> connectivity data.
>>
>>
>> 2) open the ligand pdb file and remove anything prior to the first
>> atom definition. Go to the end and remove everything past the last
>> atom definition and just add an END card.
>>
>>
>> 3) cp protein pdb to complex.pdb
>>
>> Cat ligand pdb >> complex.pdb
>>
>>
>> 4) load leap
>>
>> Source leaprc.ff99SB
>>
>> Source leaprc.gaff
>>
>> Loadamberprep ligand.prep
>>
>> Loadamberparams ligand.frcmod
>>
>> Foo = loadpdb complex.pdb
>>
>> Solvateoct foo TIP3PBOX 10.0
>>
>> Saveamberparm foo prmtop inpcrd
>>
>>
>> I hope that makes sense and is what you actually want to do I.e
>> make a prmtop and inpcrd for the solvated complex.
>>
>>
>> All the best
>>
>> Ross
>>
>>
>>
>>
>> From: owner-amber_at_scripps.edu <mailto:owner-amber_at_scripps.edu>
>> [mailto:owner-amber_at_scripps.edu <mailto:owner-amber_at_scripps.edu>] On
>> Behalf Of Sasha Buzko
>>
>> Sent: Friday, June 06, 2008 3:16 PM
>>
>> To: amber_at_scripps.edu <mailto:amber_at_scripps.edu>
>>
>> Subject: Re: AMBER: Problems simulating a protein-ligand complex
>>
>>
>> Thank you, David.
>>
>>
>> With hydrogens added in another application, the antechamber part
>> worked.
>>
>> But another issue appears when I combine the protein structure
>> with the antechamber output in xleap. The ligand is loaded as a prepin
>> file, followed by its frcmod with missing parameters. Then I load the
>> pdb file of the protein and use complex = combine { protein GNP },
>> where GNP is the name of the residue assigned to the ligand. However,
>> the ligand ends up being shifted in space far from the protein, even
>> though the initial coordinates corresponded to the complex.. I assume
>> that it's the result of the intermediate operations.. but is there a
>> way to combine the two entities into the original complex?
>>
>>
>> Thanks for any advice
>>
>>
>> Sasha
>>
>>
>>
>>
>>
>> On Fri, 2008-06-06 at 11:59 -0700, David A. Case wrote:
>>
>> On Fri, Jun 06, 2008, Sasha Buzko wrote:
>>
>> >
>> > The structure has correct connectivity and came directly from a PDB
>>
>> > file. Since the ligand PDB file is not that large, I'm pasting
>> it below.
>>
>> > Thank you for any suggestions.
>>
>>
>> You don't have any hydrogen atoms in your input structure.
>> Antechamber
>>
>> doesn't know how to add hydrogens...you need to draw them in by
>> hand, or
>>
>> use some other model building program to add all of the hydrogens.
>>
>>
>> ...hope this helps...dac
>>
>>
>>
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>>
> 

-- 
                            Dr. Adrian E. Roitberg
                              Associate Professor
                             Quantum Theory Project
                            Department of Chemistry

                  Senior Editor. Journal of Physical Chemistry
                           American Chemical Society

University of Florida                         PHONE 352 392-6972
P.O. Box 118435                               FAX   352 392-8722
Gainesville, FL 32611-8435                    Email adrian_at_qtp.ufl.edu
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