Hello Robert!
May I suggest another approach to generate new nucleotides? Use the
pyRED server:
https://upjv.q4md-forcefieldtools.org/REDServer-Development/
This tool will calculate the charge, optimize the geometry, assign the
atom types and even create the 5', 3' terminal base pairs.
The server uses a 'fragment based' approach (see
https://upjv.q4md-forcefieldtools.org/Tutorial/images2/Schema_NA1.svg).
One fragment will be the backbone atoms which is a dimethyl phosphate
(see this PDB: https://upjv.q4md-forcefieldtools.org/Tutorial/PyRED/All-frag-Nuc/Mol_red1.pdb)
The other fragment will contain the sugar and the base (see this PDB:
https://upjv.q4md-forcefieldtools.org/Tutorial/PyRED/All-frag-Nuc/Mol_red2.pdb
)
These two files will be combined together to form the nucleotide with
the required charge and atom types (based on parm10.dat).
The general workflow is like this:
- Create an account to use the pyRED server
(
https://upjv.q4md-forcefieldtools.org/register/)
- Download the dimethyl phosphate mentioned above to a directory, it
has to be named Mol_red1.pdb
- Download the nucleoside adenine example to the same directory, it
has to be named Mol_red2.pdb
- Download the Project.config example file -
https://upjv.q4md-forcefieldtools.org/Tutorial/PyRED/All-frag-Nuc/Project.config
- If you want a modification in the backbone, for example, swap an
oxygen for sulphur to make a thiophosphate, open Mol_red1.pdb in a
visualization program (DS Visualizer, Chimera, etc) and change the
atom. Save the file again with Mol_red1.pdb
- If you want a modification on the sugar or base, open the
Mol_red2.pdb and make the modification in that file. For example
if you want 2'-O-methoxy-ethyl in the C2' carbon, just add those atoms
and save the file as Mol_red2.pdb
- With the modified files, create a ZIP file that contains:
Mol_red1.pdb, Mol_red2.pdb and Project.config file
(the Project.config file will have important information about the
total charge, multiplicity and how to connect both fragments):
This part from the Project.config file:
# Define two inter-mcc between molecule 1 and molecule 2
MOLECULE-INTER-MCC1 = 0.0 | 1 2 | 10 11 12 13 | 1 2
MOLECULE-INTER-MCC1 = 0.0 | 1 2 | 1 2 3 4 | 3 4
First line says delete atoms 10 11 12 13 of the Mol_red1.pdb file
(which is the methyl cap) and delete atoms 1 2 of Mol_red2.pdb (which
is OH cap of the C5' nucleoside)
Second line is similar, delete atoms 1 2 3 4 of Mol_red2.pdb (which is
the other methyl cap of the dimethyl phosphate) and delete atoms 3 4
of Mol_red2.pdb (which is the OH cap of the C3' nucleoside)
- Submit the archive.zip file to the Server using the submit link in
the main website (
https://upjv.q4md-forcefieldtools.org/REDServer-Development/ )
- The job will run, you will get emails when the job finishes and a
link to download a tar.bz2 file with all the temporary files, log,
gaussian files, etc etc (It is quite verbose)
- Inside the tar.bz2 file, look for
PXXXX/Data-R.E.D.Server/Mol_MM/INTERCT-A_m1-c1_m2-c1.mol2 <-- This is
your new modified nucleotide
- Inside the tar.bz2 file, look for
PXXXX/Data-R.E.D.Server/Data-Default-Proj <-- you will find the frcmod
files with the required parameters (frcmod.known) and another file
(frcmod.unknown) with missing parameters that are easily extracted
from GAFF or calculated de-novo.
With this information you can generate a lib file with LEaP (saveoff
command) that you can use for Molecular Dynamics simulations.
This was a crash-course on how to use the pyRED server. Extensive
documentation for this particular situation is available here:
https://upjv.q4md-forcefieldtools.org/Tutorial/Tutorial-4.php#V3
Hope that helps!
Rodrigo.
-
On Wed, May 31, 2023 at 5:10 AM Robert Heße via AMBER <amber.ambermd.org> wrote:
>
> Dear AMBER user,
>
> recently i wrote to this mailing list regarding the fitting of missing
> atom types for modified nucleotides and after some tries i was able to
> generate a frcmod file, which takes into account both Gaff and
> AMBER(/OL15) atom types. When i wanted to refine these mixed parameters
> with mdgx, i encountered negative barrier terms:
> ----
> Generated by mdgx executing 07_fit.mdgxin.
> MASS
>
> BOND
>
> ANGL
>
> DIHE
> OS-CT-na-cc 1 46.06460 0.0 -2.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> OS-CT-na-cc 1 1.57990 0.0 1.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> OS-CT-na-ca 1 -30.72963 0.0 -2.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> OS-CT-na-ca 1 34.91051 0.0 1.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> CT-CT-na-cc 1 41.14259 0.0 -2.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> CT-CT-na-cc 1 10.25461 0.0 1.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> CT-CT-na-ca 1 -28.74262 0.0 -2.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> CT-CT-na-ca 1 54.87103 0.0 1.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> H2-CT-na-cc 1 39.28179 0.0 -2.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> H2-CT-na-cc 1 5.71388 0.0 1.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> H2-CT-na-ca 1 -32.28837 0.0 -2.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
> H2-CT-na-ca 1 49.39032 0.0 1.0 same as X -c3-na-X , penalty
> score= 0.0, Fit by mdgx
>
> IMPROPER
>
> NONB
> ----
> Those dihedral are for C2'/O4'/H1'-C1'-N9-C4/C8 of a modified
> deoxyguanosine nucleotide. I tried to adjust the Tutorial for mdgx for
> this as much as possible. I generated a total of 144 structures (2.5°)
> for sampling and then performed single point calculations via Orca. The
> Orca runs terminated normally and extracting the energies via the Speval
> Module went successful as well. The fitting report from the mdgxout-file
> also looked good, showing an improvement of the parameters:
> (1.) Energies of each system, according to the fitted parameters. Units
> on
> errors are kcal/mol. The original model's energies are compared to
> target energies after applying an offset to make the average of
> each set
> of energies for any given system equal (see Section 3).
>
> RMS Error Correlation Fitted Fitted
> Model
> System Orig Fitted Orig Fitted Terms Energy
> Diff.
> ---------------- ------- ------- ------- ------- ------ -------
> -------
> /home/hesse/DNAz 8.1688 1.5465 0.0562 0.9795 12 0.00
> 8.010
> <++>-----------------------------------------------------------------------<++>
> Sorry for the detailed information so far but im a but confused by the
> generation of negative energy barriers as i couldn't find a mistake in
> the files so far.
>
> With best regards,
> Robert Heße
>
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
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Received on Wed May 31 2023 - 08:30:03 PDT
