[gmx-users] Problem fpr building a peptide with two modified residues with amber ff -- Resolved

ABEL Stephane Stephane.ABEL at cea.fr
Mon Jan 15 19:28:59 CET 2018 

>> Would you be willing to share the exact sequence of events, commands, etc. that worked?

OK, 

Consider that the Atosiban cyclic peptide (https://fr.wikipedia.org/wiki/Atosiban) with 2 custom residues (3-Mercaptopropionyl, MEr) and ethyloxyde TYR (TYO) at Nter. The Mer is bonded to the CYS with SS bond and to TYO. Since we have no hdb for  for these residues. I first added manually the Hs in MEr and TYO with pymol with their corresponding names listed in the rtp (myAtosiban.pdb). 

My "problem" was to linked the Mer and TYO  and TYO with ILE by two peptide bonds and thus form a SS bond with Mer and CYS

1) consider the Mer and TYO as Protein residues and add  in residuetypes.dat the following lines

 MER Protein
 TYO Protein
 
 2) construct the corresponding rtp for these two custom residues (the RESP charges were derived with PyRED) Disclaimer ; these charges are "absolutely not" tested 
 
  TYO rtp 
  ; RESP partial charges derived from PyRED
  ; residue has similar structure than TYR
[ TYO ]
 [ atoms ]
     N    N    -0.5197     1
     H    H     0.2770     2
    CA    CX    0.4385     3
    HA    H1    0.0423     4
    CB    CT   -0.1978     5
   HB1    HC    0.0698     6
   HB2    HC    0.0698     7
    CG    CA    0.0563     8
   CD1    CA   -0.2130     9
   HD1    HA    0.1417    10
   CE1    CA   -0.1627    11
   HE1    HA    0.1373    12
   CZ     C     0.2714    13
   OE     OS   -0.3844    14
   C2     CT    0.1715    15
   H21    H1    0.0313    16
   H22    H1    0.0313    17
   C3     CT   -0.0526    18
   H31    HC    0.0194    19
   H32    HC    0.0194    20
   H33    HC    0.0194    21
   CD2    CA   -0.2130    22
   HD2    HA    0.1417    23
   CE2    CA   -0.1627    24
   HE2    HA    0.1373    25
    C     C     0.4047    26 ; CO in PyRED
    O     O    -0.5742    27
	
	[ bonds ]
     N     H
     N    CA
    CA    HA
    CA    CB
    CA     C
    CB   HB1
    CB   HB2
    CB    CG
    CG   CD1
    CG   CD2
   CD1   HD1
   CD1   CE1
   CE1   HE1
   CE1    CZ
    CZ    OE
    OE    C2
    C2    H21
    C2    H22
    C2    C3
    C3    H31
    C3    H32
    C3    H33
    CZ    CE2
   CE2   HE2
   CE2   CD2
   CD2   HD2
     C     O
     C    +N  ---> here the trick to make a peptide bond with ILE
	
 [ impropers ]
    -C    CA     N     H
    CA    +N     C     O
    CG   CE2   CD2   HD2
    CZ   CD2   CE2   HE2
   CD1    CZ   CE1   HE1
    CG   CE1   CD1   HD1
   CD1   CD2    CG    CB
   CE1   CE2    CZ    OE
   
 MER 
 
 ; Mercapto
;
;              S1
;               |
;          H21-C2-H22
;               |
;           H31-C3-H32
;               |
;               C=O

; RESP partial charges derived from PyRED

[ MER ]
 [ atoms ]
    S1  S     -0.1994  1
    C2  CT     0.0424  2   ; same as C3 in PyRED
    H21 H1     0.0631  3   ; same as H31 in PyRED
    H22 H1     0.0631  4   ; same as H32 in PyRED
    C3  CT    -0.0157  5   ; same as C4 in PyRED
    H31 H1     0.0295  6   ; same as H41 in PyRED
    H32 H1     0.0295  7   ; same as H42 in PyRED
    C   C      0.5373  8   ; same as C2 in PyRED
    O   O     -0.5498  9   ; same as O1 in PyRED

[ bonds ]
     S1   C2
	 C2   H21
     C2   H22
     C2   C3
     C3   H31
     C3   H32
     C3   C
     C    O
     C   +N  --> here the trick to make a peptide bond with TYO

 [ impropers ]
    C3    +N     C     O

3) to make a SS bond between Mer and CYS. Add in the specbondat the following line 

1
MER     S1      1       CYX     SG      1       0.20380     MER  CYX  ;; S-S bond distance in Amber

And to finish use the following command to construct the top file 

mpirun -np 1 gmx_mpi pdb2gmx -f myAtosiban.pdb -p myAtosiban.top -o myAtosiban_H.pdb -i myAtosiban_posre.itp -missing -rtpres

and perform a short minimization to check if the three bonds are correctly set (not broken). 

Stéphane 

------------------------------

Message: 2
Date: Mon, 15 Jan 2018 12:42:16 -0500
From: Justin Lemkul <jalemkul at vt.edu>
To: gmx-users at gromacs.org
Subject: Re: [gmx-users] Problem fpr building a peptide with two
        modified residues with amber ff -- Resolved
Message-ID: <a1922ea9-4776-a450-7bea-5e141850f0d2 at vt.edu>
Content-Type: text/plain; charset=utf-8; format=flowed



On 1/15/18 12:31 PM, ABEL Stephane wrote:
> Hello,
>
> I have finally resolved my problem thank to Justin .

Would you be willing to share the exact sequence of events, commands,
etc. that worked? As I mentioned before, these threads often trail off
or end unresolved, so while it is nice that you solved your own problem,
it would be beneficial to the community to document how you did it so
that others might learn.

-Justin

> Bye
> ------------------------------
>
> Message: 2
> Date: Sun, 14 Jan 2018 17:36:21 -0500
> From: Justin Lemkul <jalemkul at vt.edu>
> To: gmx-users at gromacs.org
> Subject: Re: [gmx-users] Problem fpr building a peptide with two
>          modified residues with amber ff
> Message-ID: <b7a10948-61d2-5b3f-b062-6630785c61af at vt.edu>
> Content-Type: text/plain; charset=utf-8; format=flowed
>
>
>
> On 1/14/18 12:04 PM, ABEL Stephane wrote:
>> Thank you, Justin for your interest to my problem,
>>
>> But even if I use the -missing argument*, pdb2gmx still wants to add an Nter ILE instead of a central a simple ILE :((
> Ile should not be treated as a terminal residue, and it wasn't in the
> screen output you provided before after adding your custom residues to
> residuetypes.dat. That's a prerequisite if you want anything to work.
> Getting the connectivity right after dealing with the custom residues is
> the next problem after that.
>
> -Justin
>
>> *gmx_mpi pdb2gmx -f Atosiban_box_ctr.pdb -p Atosiban_amber14sb.top -o Atosiban_amber14sb.pdb -i Atosiban_posre.itp -missing
>>
>> I will try to search a workaround
>>
>> Best
>>
>> St?phane
>>
>> ________________________________________
>> De : ABEL Stephane
>> Envoy? : dimanche 14 janvier 2018 16:52
>> ? : gromacs.org_gmx-users at maillist.sys.kth.se
>> Objet : RE:gromacs.org_gmx-users Digest, Vol 165, Issue 50
>>
>> Thanks Justin
>>
>> First I forgot to say that I am building a cyclic peptide (Atosiban, https://fr.wikipedia.org/wiki/Atosiban). I construct two RTP for the  MER (3-Mercaptopropionyl-) and TYO (ethoxy tyrosine. And they are correct since the two residues are well constructed and linked together with pdb2gmx as it is shown If I consider the ILE as NILE
>>
>> For linking the MER and CYX I define a bond with the specbond.dat (the corresponding bond is shown in the  pdb2gmx output). The only problem I have is that NILE residue is chosen instead of ILE
>>
>> How to resolve this problem and to force pdb2gmx to use ILE ? It is strange or I found a subtle error I cannot find.
>>
>> St?phane
>>
>>
>>
>>
>> ------------------------------
>>
>> Message: 3
>> Date: Sun, 14 Jan 2018 10:34:08 -0500
>> From: Justin Lemkul <jalemkul at vt.edu>
>> To: gmx-users at gromacs.org
>> Subject: Re: [gmx-users] Problem fpr building a peptide with two
>>           modified residues with amber ff
>> Message-ID: <541ddbd0-378e-16eb-79a4-f161235d4d22 at vt.edu>
>> Content-Type: text/plain; charset=utf-8; format=flowed
>>
>>
>>
>> On 1/14/18 10:04 AM, ABEL Stephane wrote:
>>> Hi Justin
>>>
>>> I have added the TYO and MER residue as Protein is the residuetypes.dat. And the the following output with pdb2gmx. I select 2 and 6
>>>
>>> ##########
>>>      gmx_mpi pdb2gmx -f Atosiban_box_ctr.pdb -p Atosiban_amber14sb.top -o Atosiban_amber14sb.pdb -i Atosiban_posre.itp -rtpres yes
>>>
>>>
>>> Select the Force Field:
>>>    From '/ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top/':
>>>     1: Amber12sb ff99SB + new backbone and side chain torsion for protein
>>>     2: AMBER14SB_parmbsc1 (ff14SB for protein + parmbsc1 for DNA)
>>>     3: AMBER94 BCL force field (J. Comp. Chem. 2012, 33, 1969?1980)
>>>     4: CHARMM36 all-atom force field (July 2017)
>>>     5: CHARMM36 all-atom force field, surfactants and pigments
>>>     6: GLYCAM06 force field for alkylglycosides and RG1 (2011, J. Phys. Chem. B 2011, 115, 487-499 )
>>>     7: GROMOS96 2016H66 force field (J. Chem. Theory. Comput., 2016, 12, 3825?3850)
>>>     8: GROMOS96 53a6 force field with PVP (JCC 2004 vol 25 pag 1656 and J. Phys. Chem. C, 2015, 119 (14), pp 7888?7899)
>>>     9: GROMOS96 53a6carbo force field (JCC 2011 vol 32 pag 998, doi 10.1002/jcc.21675)
>>> 10: GROMOS96 54a7 force field (Eur. Biophys. J. (2011), 40,, 843-856, DOI: 10.1007/s00249-011-0700-9)
>>>    From '/ccc/products/gromacs-5.1.2/default/share/gromacs/top':
>>> 11: AMBER03 protein, nucleic AMBER94 (Duan et al., J. Comp. Chem. 24, 1999-2012, 2003)
>>> 12: AMBER94 force field (Cornell et al., JACS 117, 5179-5197, 1995)
>>> 13: AMBER96 protein, nucleic AMBER94 (Kollman et al., Acc. Chem. Res. 29, 461-469, 1996)
>>> 14: AMBER99 protein, nucleic AMBER94 (Wang et al., J. Comp. Chem. 21, 1049-1074, 2000)
>>> 15: AMBER99SB protein, nucleic AMBER94 (Hornak et al., Proteins 65, 712-725, 2006)
>>> 16: AMBER99SB-ILDN protein, nucleic AMBER94 (Lindorff-Larsen et al., Proteins 78, 1950-58, 2010)
>>> 17: AMBERGS force field (Garcia & Sanbonmatsu, PNAS 99, 2782-2787, 2002)
>>> 18: CHARMM27 all-atom force field (CHARM22 plus CMAP for proteins)
>>> 19: GROMOS96 43a1 force field
>>> 20: GROMOS96 43a2 force field (improved alkane dihedrals)
>>> 21: GROMOS96 45a3 force field (Schuler JCC 2001 22 1205)
>>> 22: GROMOS96 53a5 force field (JCC 2004 vol 25 pag 1656)
>>> 23: GROMOS96 53a6 force field (JCC 2004 vol 25 pag 1656)
>>> 24: GROMOS96 54a7 force field (Eur. Biophys. J. (2011), 40,, 843-856, DOI: 10.1007/s00249-011-0700-9)
>>> 25: OPLS-AA/L all-atom force field (2001 aminoacid dihedrals)
>>> 2
>>>
>>> Using the Amber14sb_parmbsc1 force field in directory /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff
>>>
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/watermodels.dat
>>>
>>> Select the Water Model:
>>>     1: TIP3P     TIP 3-point, recommended
>>>     2: TIP4P     TIP 4-point
>>>     3: TIP4P-Ew  TIP 4-point optimized with Ewald
>>>     4: SPC       simple point charge
>>>     5: SPC/E     extended simple point charge
>>>     6: None
>>> 6
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/aminoacids.r2b
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/dna.r2b
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/rna.r2b
>>> Reading Atosiban_box_ctr.pdb...
>>> Read 'GROningen MAchine for Chemical Simulation', 85 atoms
>>> Analyzing pdb file
>>> Splitting chemical chains based on TER records or chain id changing.
>>> There are 1 chains and 0 blocks of water and 10 residues with 85 atoms
>>>
>>>      chain  #res #atoms
>>>      1 'A'    10     85
>>>
>>> All occupancies are one
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/atomtypes.atp
>>> Atomtype 89Reading residue database... (amber14sb_parmbsc1)
>>>
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/Merca.rtp
>>> Residue 1
>>> Sorting it all out...
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/TYO.rtp
>>> Residue 2
>>> Sorting it all out...
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/aminoacids.rtp
>>> Residue 95
>>> Sorting it all out...
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/dna.rtp
>>> Residue 111
>>> Sorting it all out...
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/rna.rtp
>>> Residue 127
>>> Sorting it all out...
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/aminoacids.hdb
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/dna.hdb
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/rna.hdb
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/aminoacids.n.tdb
>>> Opening force field file /ccc/work/cont003/dsv/abel01/ForceFields/GMX_ForceFields/top//amber14sb_parmbsc1.ff/aminoacids.c.tdb
>>>
>>> Back Off! I just backed up Atosiban_amber14sb.top to ./#Atosiban_amber14sb.top.6#
>>> Processing chain 1 'A' (85 atoms, 10 residues)
>>> Identified residue MER1 as a starting terminus.
>>> Identified residue NH210 as a ending terminus.
>>> 1 out of 1 lines of specbond.dat converted successfully
>>> Special Atom Distance matrix:
>>>                        MER1
>>>                         S11
>>>        CYX6    SG63   0.200
>>> Linking MER-1 S1-1 and CYX-6 SG-63...
>>>
>>> -------------------------------------------------------
>>> Program gmx pdb2gmx, VERSION 5.1.2
>>> Source code file: /tmp/gromacs/5.1.2/iomkl-156233.188/gromacs-5.1.2/src/gromacs/gmxpreprocess/pdb2top.cpp, line: 1083
>>>
>>> Fatal error:
>>> There is a dangling bond at at least one of the terminal ends and the force field does not provide terminal entries or files. Fix your terminal residues so that they match the residue database (.rtp) entries, or provide terminal database entries (.tdb).
>>> For more information and tips for troubleshooting, please check the GROMACS
>>> website at http://www.gromacs.org/Documentation/Errors
>>> -------------------------------------------------------
>>> ####
>>>
>>> Now indeed the MER and TYO as recognized as residues but I still obtain the dangling bond error
>> The AMBER force fields are unique in that they do not support terminal
>> group patching; your residue definitions for any terminal residues must
>> be complete. I suspect your N-terminal MER residue does not have the
>> proper -NH3+ terminus already built, so when pdb2gmx checks, it finds
>> missing atoms. You need to specifically parametrize this residue in its
>> terminal, not internal, form and supply that as your .rtp entry.
>>
>> -Justin
>>
>> --
>> ==================================================
>>
>> Justin A. Lemkul, Ph.D.
>> Assistant Professor
>> Virginia Tech Department of Biochemistry
>>
>> 303 Engel Hall
>> 340 West Campus Dr.
>> Blacksburg, VA 24061
>>
>> jalemkul at vt.edu | (540) 231-3129
>> http://www.biochem.vt.edu/people/faculty/JustinLemkul.html
>>
>> ==================================================
>>
>>
>>
>> ------------------------------
>>
>> --
>> Gromacs Users mailing list
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>> * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting!
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>> End of gromacs.org_gmx-users Digest, Vol 165, Issue 50
>> ******************************************************
>>
>>
>> ------------------------------
>>
>> Message: 2
>> Date: Sun, 14 Jan 2018 10:55:19 -0500
>> From: Justin Lemkul <jalemkul at vt.edu>
>> To: gmx-users at gromacs.org
>> Subject: Re: [gmx-users] gromacs.org_gmx-users Digest, Vol 165, Issue
>>           50
>> Message-ID: <d44769fa-da75-16f2-fbae-4ff815bb13c0 at vt.edu>
>> Content-Type: text/plain; charset=utf-8; format=flowed
>>
>>
>>
>> On 1/14/18 10:52 AM, ABEL Stephane wrote:
>>> Thanks Justin
>>>
>>> First I forgot to say that I am building a cyclic peptide (Atosiban, https://fr.wikipedia.org/wiki/Atosiban). I construct two RTP for the  MER (3-Mercaptopropionyl-) and TYO (ethoxy tyrosine. And they are correct since the two residues are well constructed and linked together with pdb2gmx as it is shown If I consider the ILE as NILE
>>>
>>> For linking the MER and CYX I define a bond with the specbond.dat (the corresponding bond is shown in the  pdb2gmx output). The only problem I have is that NILE residue is chosen instead of ILE
>>>
>>> How to resolve this problem and to force pdb2gmx to use ILE ? It is strange or I found a subtle error I cannot find.
>> I've never dealt with cyclic peptides in GROMACS and most threads about
>> them tend to die off without resolution. It's not something pdb2gmx does
>> well. Presumably you could use the -missing flat (very dangerous!) and
>> then verify that the topology has all the special bonds it needs.
>>
>> -Justin
>>
>> --
>> ==================================================
>>
>> Justin A. Lemkul, Ph.D.
>> Assistant Professor
>> Virginia Tech Department of Biochemistry
>>
>> 303 Engel Hall
>> 340 West Campus Dr.
>> Blacksburg, VA 24061
>>
>> jalemkul at vt.edu | (540) 231-3129
>> http://www.biochem.vt.edu/people/faculty/JustinLemkul.html
>>
>> ==================================================
>>

--
==================================================

Justin A. Lemkul, Ph.D.
Assistant Professor
Virginia Tech Department of Biochemistry

303 Engel Hall
340 West Campus Dr.
Blacksburg, VA 24061

jalemkul at vt.edu | (540) 231-3129
http://www.biochem.vt.edu/people/faculty/JustinLemkul.html

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



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