[gmx-users] Disulphide bonded cyclic peptides

Sahil Lall slall at ncbs.res.in
Fri Nov 29 08:29:48 CET 2019 

Hello, 

Thank you for your suggestions, gave me some insight into my own work.
However, the problem still persists.

> With the option -ignh, you request pdb2gmx to add H atom. Thus, if you have  already H atoms in the pdb I suggest to remove the option -ignh.

I had already tried removing the -ignh option before posting this here
but did not find success.

Did you try also without -ter? 

Removing the -ter option does not work in any combination. It always
overrides everything else and breaks the cyclising peptide bond into
NH3+ and COO-. 

.

> Another option could be to remove the extra H from gro/pdb file you got from pdb2gmx, remove H, (if you want, fix the atom number using editconf), then try to use the so obtained pdb/gro file as input to pdb2gmx (without -ter -ignh)

So this also does not work. pdb2gmx breaks the peptide bond without the
-ter option. 

I tried putting a new entry in the OPLS aminoacids.n.tdb file as you
suggested. I used the opls_910 planar hydrogen for secondary amines as
shown below 

[ CYS2-NH ]
[ replace ]
N opls_900 14.0027 -0.9
CA opls_912B 12.011 0.12
[ add ]
1 1 H N CA C
opls_910 1.008 0.38
[ delete ]
H 

Now I can get the peptide bond correctly but the system is charged.
Output below: 

Identified residue CYS1 as a starting terminus.
Identified residue CYS6 as a ending terminus.
2 out of 2 lines of specbond.dat converted successfully
Special Atom Distance matrix:
CYS1 CYS1 CYS1 CYS6 CYS6
N1 C3 SG6 N87 C89
CYS1 C3 0.244
CYS1 SG6 0.312 0.419
CYS6 N87 0.335 0.510 0.486
CYS6 C89 0.136 0.373 0.322 0.239
CYS6 SG92 0.387 0.482 0.205 0.420 0.365
Linking CYS-1 N-1 and CYS-6 C-89...
Linking CYS-1 SG-6 and CYS-6 SG-92...
Select start terminus type for CYS-1
0: CYS2-NH
1: NH3+
2: ZWITTERION_NH3+ (only use with zwitterions containing exactly one
residue)
3: NH2
4: None
0
Start terminus CYS-1: CYS2-NH
Select end terminus type for CYS-6
0: COO-
1: ZWITTERION_COO- (only use with zwitterions containing exactly one
residue)
2: COOH
3: None
3
End terminus CYS-6: None
Checking for duplicate atoms....
Generating any missing hydrogen atoms and/or adding termini.
Now there are 6 residues with 96 atoms
Making bonds...
Number of bonds was 99, now 98
Generating angles, dihedrals and pairs...
Before cleaning: 258 pairs
Before cleaning: 258 dihedrals
Keeping all generated dihedrals
Making cmap torsions...There are 258 dihedrals, 21 impropers, 174 angles
255 pairs, 98 bonds and 0 virtual sites
Total mass 734.892 a.m.u.
Total charge -0.420 e
Writing topology 

Any ideas? 

Extremely thankful 

Sahil 

On 2019-11-28 20:15, Alessandra Villa wrote:

> Hi again,
> 
> On Thu, Nov 28, 2019 at 11:06 AM Sahil Lall <slall at ncbs.res.in> wrote:
> 
> Hello,
> 
> I am extremely thankful for your suggestions, but I have a few concerns
> with your advice as stated below.
> 
> Hi,
> Below some suggestion that may help you.
> 
> On Wed, Nov 27, 2019 at 7:44 AM Sahil Lall <slall at ncbs.res.in> wrote:
> 
> Dear community,
> 
> I want to use the OPLS-AA ff to understand the dynamics of a cyclic
> peptide with terminal Cystines that are disulphide linked. To cyclise
> the N- and C- termini, I used a special bond in a specbond.dat file
> placed in my working directory.
> 
> 2
> CYS N 1 CYS C 1 0.14 CYS CYS
> CYS SG 1 CYS SG 1 0.2 CYS2 CYS2
> 
> and after the pdb2gmx command I get the following response
> 
> Identified residue CYS2 as a starting terminus.
> Identified residue CYS7 as a ending terminus.
> 2 out of 2 lines of specbond.dat converted successfully
> Special Atom Distance matrix:
> CYS2    CYS2    CYS2    CYS7    CYS7
> N1      C3     SG6     N45     C47
> CYS2      C3   0.244
> CYS2     SG6   0.312   0.419
> CYS7     N45   0.335   0.510   0.486
> CYS7     C47   0.136   0.373   0.322   0.239
> CYS7    SG50   0.387   0.482   0.205   0.420   0.365
> Linking CYS-2 N-1 and CYS-7 C-47...
> Linking CYS-2 SG-6 and CYS-7 SG-50...
> 
> However, the problem arises with the -ter flag in the pdb2gmx command
> 
> pdb2gmx -f in.pdb -o out.gro -ter -ignh
> 
> With the option -ignh, you request pdb2gmx to add H atom. Thus, if you have  already H atoms in the pdb I suggest to remove the option -ignh.

I had already tried removing the -ignh option before posting this here
but did not find success.

Did you try also without -ter? 

>> In alternative,  you could try add a new entry in the file opls force
> field 
> 
>> file aminoacids.n.tdb for your CYS termini (e.i in place of NH2 put NH).
> In 
> 
>> alternative you can use the file that you got using NH2 as N-terminus,
> and 
> 
>> manually remove the extra H you  have connected to N (both from top and
> gro 
> 
>> file). This operation requires to be very careful since you have to
> remove 
> 
>> the correct H.
> 
> If I remove the extra hydrogen after getting the pdb2gmx output, will I
> not have to edit the topology file also?

Yes you should fix also the top file, including  removing all the
interactions that involve the removed H

Another option could be to remove the extra H from gro/pdb file you got
from pdb2gmx, remove H, (if you want, fix the atom number using
editconf),
then try to use the so obtained pdb/gro file as input to pdb2gmx
(without
-ter -ignh)

> And will changing the CYS
> termini in the force field .tdb file not mess with anything else as far
> as the force field parameters are concerned?
 If properly done, no

Best regards
Alessandra

> Thankful,
> 
> Sahil
> 
> Best regards
> Alessandra
> 
> The output is fine and links the terminal Cystines and putting a
 disulphide bond between them as shown above. But doesn't seem to be 

>> happy with the -ter command.
>> 
>> Select start terminus type for CYS-2
>> 0: NH3+
>> 1: ZWITTERION_NH3+ (only use with zwitterions containing exactly one
>> residue)
>> 2: NH2
>> 3: None
>> 3
>> Start terminus CYS-2: None
>> Select end terminus type for CYS-7
>> 0: COO-
>> 1: ZWITTERION_COO- (only use with zwitterions containing exactly one
>> residue)
>> 2: COOH
>> 3: None
>> 3
>> End terminus CYS-7: None
>> 
>> -------------------------------------------------------
>> Program pdb2gmx, VERSION 4.6.7
>> Source code file:
>> /home/ncbs/Downloads/gromacs-4.6.7/src/kernel/pdb2top.c, line: 1109
>> 
>> Fatal error:
>> There is a dangling bond at at least one of the terminal ends. Fix your
>> coordinate file, add a new terminal database entry (.tdb), or select the
>> proper existing terminal entry.
>> For more information and tips for troubleshooting, please check the
>> GROMACS
>> website at http://www.gromacs.org/Documentation/Errors
>> -------------------------------------------------------
>> 
>> I cannot understand what is going wrong. The command only works if I
>> choose NH2 as my N-terminus, however that in principle violates the
>> neutrality of the system.
> 
>> Thanks,
>> 
>> Sahil
>> --
 --
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