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#34786 02/09/15 05:42 PM
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mgleed Offline OP
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Hello,

I'm trying to help a fellow researcher to create charmm top/par for several unnatural amino acids he has synthesized. I have some experience with simple amino-acid adjustments (such as making PTHR based on THR and PTYR), and ligand parameterization with cgenff (paramchem.org).

One of the amino acids is ILE, but with a double bond connecting the alpha and beta carbons rather than a single bond. I figure the geometry of such an AA would be substantially different from ILE, such that adding the term DOUBLE to the topology wouldn't suffice and significant new atom typing with QM parameters, etc. might be necessary.

If any of you have any pointers on how you would approach parameterizing this example UAA, or if you could point me to any other helpful tutorials, webservers, or recent resources for performing such a task, I would appreciate it very much.

Thank you!

Last edited by mgleed; 02/09/15 05:45 PM.
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DOUBLE does not carry any special significance, it just means BOND.
If you look at the standard representation of the empirical energy function used in MM or MD you will see that the parameters in the function are what is important, and this is exactly is contained in the force field files.

Try paramchem.org to get a first guess.


Lennart Nilsson
Karolinska Institutet
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The choice of the model compound used with ParamChem can be important here, esp. for polymer residues. I would probably start with N-methyl and acetyl groups representing the adjoining residues. (This assumes the novel residue is usually not one of the termini, or has a chain cap such as N-methyl and/or acetyl.)


Rick Venable
computational chemist

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mgleed Offline OP
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Thank you both for the helpful suggestions. I have put the molecule suggested by Dr. Venable through paramchem.

This part of the process isn't what seems most difficult to me, it's deciding how to apply the paramchem output to make a new residue and its corresponding parameters. If the paramchem output for the example UAA (ILE with double-bonded CA=CB) were nearly ideal (for simplicity's sake), how would you approach applying the output to make a new residue? Preserve everything but the extra N-methyl and acetyl atoms? Would you try to use the build-in ILE top/par as templates (to perhaps preserve some protein parameters) and make corresponding adjustments based on the output?

Here is the paramchem output for the ILE-based UAA (with a little chart of the molecule to establish atom names). I plan to optimize charges and parameters with Gaussian.
Code:
! C8(H11-13)
! |
! N2(H10)
! |
! C5==O2  C3(H1-3)
! |       |
! C2======C1--C4(H4-5)
! |           |
! N1(H6)      C9(H14-16)
! |
! C6==O1
! |
! C7(H7-9)

Click to reveal..

* Toppar stream file generated by
* CHARMM General Force Field (CGenFF) program version 0.9.7.1 beta
* For use with CGenFF version 2b8
*

read rtf card append
* Topologies generated by
* CHARMM General Force Field (CGenFF) program version 0.9.7.1 beta
*
36 1

! "penalty" is the highest penalty score of the associated parameters.
! Penalties lower than 10 indicate the analogy is fair; penalties between 10
! and 50 mean some basic validation is recommended; penalties higher than
! 50 indicate poor analogy and mandate extensive validation/optimization.

RESI Y001 0.000 ! param penalty= 162.500 ; charge penalty= 168.926
GROUP ! CHARGE CH_PENALTY
ATOM C1 CG2DC1 0.244 ! 43.032
ATOM C2 CG2D1O 0.097 ! 168.926
ATOM C3 CG331 -0.304 ! 3.109
ATOM C4 CG321 -0.258 ! 3.390
ATOM C5 CG2O1 0.480 ! 53.051
ATOM N1 NG2S1 -0.533 ! 167.456
ATOM C6 CG2O1 0.528 ! 14.425
ATOM C7 CG331 -0.275 ! 8.367
ATOM O1 OG2D1 -0.524 ! 9.391
ATOM O2 OG2D1 -0.505 ! 12.776
ATOM N2 NG2S1 -0.473 ! 11.719
ATOM C8 CG331 -0.082 ! 1.824
ATOM H1 HGA3 0.090 ! 0.175
ATOM H2 HGA3 0.090 ! 0.175
ATOM H3 HGA3 0.090 ! 0.175
ATOM H4 HGA2 0.090 ! 0.000
ATOM C9 CG331 -0.269 ! 1.421
ATOM H5 HGA2 0.090 ! 0.000
ATOM H6 HGP1 0.321 ! 9.083
ATOM H7 HGA3 0.090 ! 0.000
ATOM H8 HGA3 0.090 ! 0.000
ATOM H9 HGA3 0.090 ! 0.000
ATOM H10 HGP1 0.293 ! 1.596
ATOM H11 HGA3 0.090 ! 0.000
ATOM H12 HGA3 0.090 ! 0.000
ATOM H13 HGA3 0.090 ! 0.000
ATOM H14 HGA3 0.090 ! 0.025
ATOM H15 HGA3 0.090 ! 0.025
ATOM H16 HGA3 0.090 ! 0.025

BOND C1 C2
BOND C1 C3
BOND C1 C4
BOND C2 C5
BOND C2 N1
BOND C3 H1
BOND C3 H2
BOND C3 H3
BOND C4 H4
BOND C4 C9
BOND C4 H5
BOND C5 O2
BOND C5 N2
BOND N1 C6
BOND N1 H6
BOND C6 C7
BOND C6 O1
BOND C7 H7
BOND C7 H8
BOND C7 H9
BOND N2 C8
BOND N2 H10
BOND C8 H11
BOND C8 H12
BOND C8 H13
BOND C9 H14
BOND C9 H15
BOND C9 H16
IMPR C2 C1 C5 N1
IMPR C5 C2 N2 O2
IMPR C6 C7 N1 O1

END

read param card flex append
* Parameters generated by analogy by
* CHARMM General Force Field (CGenFF) program version 0.9.7.1 beta
*

! Penalties lower than 10 indicate the analogy is fair; penalties between 10
! and 50 mean some basic validation is recommended; penalties higher than
! 50 indicate poor analogy and mandate extensive validation/optimization.

BONDS
CG2D1O CG2O1 440.00 1.4890 ! Y001 , from CG2DC1 CG2O1, penalty= 40
CG2D1O NG2S1 370.00 1.3450 ! Y001 , from CG2O1 NG2S1, penalty= 70

ANGLES
CG2DC1 CG2D1O CG2O1 48.00 123.50 ! Y001 , from CG2DC1 CG2DC1 CG2O1, penalty= 40
CG2DC1 CG2D1O NG2S1 60.00 122.00 ! Y001 , from CG2DC1 CG2D1O NG311, penalty= 66
CG2O1 CG2D1O NG2S1 80.00 116.50 ! Y001 , from CG2R61 CG2O1 NG2S1, penalty= 95
CG2D1O CG2DC1 CG331 43.50 126.50 ! Y001 , from CG2D1O CG2DC1 CG321, penalty= 0.9
CG2D1O CG2O1 NG2S1 80.00 116.50 ! Y001 , from CG2DC1 CG2O1 NG2S1, penalty= 3.5
CG2D1O CG2O1 OG2D1 80.00 122.50 ! Y001 , from CG2DC1 CG2O1 OG2D1, penalty= 3.5
CG2DC1 CG321 CG331 32.00 112.20 ! Y001 , from CG2D1 CG321 CG331, penalty= 0.5
CG2D1O NG2S1 CG2O1 50.00 120.00 ! Y001 , from CG2O1 NG2S1 CG2R61, penalty= 21
CG2D1O NG2S1 HGP1 34.00 117.00 ! Y001 , from CG2R61 NG2S1 HGP1, penalty= 21

DIHEDRALS
CG2O1 CG2D1O CG2DC1 CG321 0.5600 1 180.00 ! Y001 , from CG2O1 CG2DC1 CG2DC1 CG331, penalty= 40.9
CG2O1 CG2D1O CG2DC1 CG321 7.0000 2 180.00 ! Y001 , from CG2O1 CG2DC1 CG2DC1 CG331, penalty= 40.9
CG2O1 CG2D1O CG2DC1 CG331 0.5600 1 180.00 ! Y001 , from CG2O1 CG2DC1 CG2DC1 CG331, penalty= 40
CG2O1 CG2D1O CG2DC1 CG331 7.0000 2 180.00 ! Y001 , from CG2O1 CG2DC1 CG2DC1 CG331, penalty= 40
NG2S1 CG2D1O CG2DC1 CG321 2.5000 2 180.00 ! Y001 , from NG311 CG2D1O CG2DC1 CG321, penalty= 66
NG2S1 CG2D1O CG2DC1 CG331 2.5000 2 180.00 ! Y001 , from NG311 CG2D1O CG2DC1 CG321, penalty= 66.9
CG2DC1 CG2D1O CG2O1 NG2S1 0.7000 1 0.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 NG2S1, penalty= 40
CG2DC1 CG2D1O CG2O1 NG2S1 1.2000 2 180.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 NG2S1, penalty= 40
CG2DC1 CG2D1O CG2O1 NG2S1 0.1000 3 0.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 NG2S1, penalty= 40
CG2DC1 CG2D1O CG2O1 NG2S1 0.1500 4 0.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 NG2S1, penalty= 40
CG2DC1 CG2D1O CG2O1 OG2D1 0.7000 1 180.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 OG2D1, penalty= 40
CG2DC1 CG2D1O CG2O1 OG2D1 1.2000 2 180.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 OG2D1, penalty= 40
CG2DC1 CG2D1O CG2O1 OG2D1 0.1000 3 180.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 OG2D1, penalty= 40
CG2DC1 CG2D1O CG2O1 OG2D1 0.2000 4 0.00 ! Y001 , from CG2DC1 CG2DC1 CG2O1 OG2D1, penalty= 40
NG2S1 CG2D1O CG2O1 NG2S1 0.5000 2 180.00 ! Y001 , from CG321 CG2DC1 CG2O1 NG2S2, penalty= 110
NG2S1 CG2D1O CG2O1 NG2S1 0.3500 3 180.00 ! Y001 , from CG321 CG2DC1 CG2O1 NG2S2, penalty= 110
NG2S1 CG2D1O CG2O1 NG2S1 0.4000 6 0.00 ! Y001 , from CG321 CG2DC1 CG2O1 NG2S2, penalty= 110
NG2S1 CG2D1O CG2O1 OG2D1 1.0000 2 180.00 ! Y001 , from CG321 CG2DC1 CG2O1 OG2D1, penalty= 109
NG2S1 CG2D1O CG2O1 OG2D1 1.0000 3 0.00 ! Y001 , from CG321 CG2DC1 CG2O1 OG2D1, penalty= 109
NG2S1 CG2D1O CG2O1 OG2D1 0.4000 6 0.00 ! Y001 , from CG321 CG2DC1 CG2O1 OG2D1, penalty= 109
CG2DC1 CG2D1O NG2S1 CG2O1 1.6000 1 0.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 CG2R61, penalty= 135
CG2DC1 CG2D1O NG2S1 CG2O1 2.5000 2 180.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 CG2R61, penalty= 135
CG2DC1 CG2D1O NG2S1 HGP1 2.5000 2 180.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 HGP1, penalty= 110
CG2O1 CG2D1O NG2S1 CG2O1 1.6000 1 0.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 CG2R61, penalty= 123.5
CG2O1 CG2D1O NG2S1 CG2O1 2.5000 2 180.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 CG2R61, penalty= 123.5
CG2O1 CG2D1O NG2S1 HGP1 2.5000 2 180.00 ! Y001 , from CG2R61 CG2O1 NG2S1 HGP1, penalty= 95
CG2D1O CG2DC1 CG321 CG331 0.5000 2 0.00 ! Y001 , from CG2DC1 CG2DC1 CG321 CG321, penalty= 4.4
CG2D1O CG2DC1 CG321 CG331 0.3000 3 0.00 ! Y001 , from CG2DC1 CG2DC1 CG321 CG321, penalty= 4.4
CG331 CG2DC1 CG321 CG331 0.1900 3 0.00 ! Y001 , from CG331 CG2DC2 CG321 CG321, penalty= 0.9
CG2D1O CG2DC1 CG331 HGA3 0.3000 3 180.00 ! Y001 , from CG2DC1 CG2DC1 CG331 HGA3, penalty= 3.5
CG2D1O CG2O1 NG2S1 CG331 1.6000 1 0.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 CG331, penalty= 3.5
CG2D1O CG2O1 NG2S1 CG331 2.5000 2 180.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 CG331, penalty= 3.5
CG2D1O CG2O1 NG2S1 HGP1 2.5000 2 180.00 ! Y001 , from CG2DC1 CG2O1 NG2S1 HGP1, penalty= 3.5
CG331 CG2O1 NG2S1 CG2D1O 1.6000 1 0.00 ! Y001 , from CG331 CG2O1 NG2S1 CG2R61, penalty= 21
CG331 CG2O1 NG2S1 CG2D1O 2.5000 2 180.00 ! Y001 , from CG331 CG2O1 NG2S1 CG2R61, penalty= 21
OG2D1 CG2O1 NG2S1 CG2D1O 2.5000 2 180.00 ! Y001 , from OG2D1 CG2O1 NG2S1 CG2R61, penalty= 21
CG2DC1 CG321 CG331 HGA3 0.1600 3 0.00 ! Y001 , from CG2D1 CG321 CG331 HGA3, penalty= 0.5

IMPROPERS
CG2D1O CG2DC1 CG2O1 NG2S1 72.0000 0 0.00 ! Y001 , from CG2O5 CG2O3 CG2R61 OG2D3, penalty= 162.5
CG2O1 CG2D1O NG2S1 OG2D1 120.0000 0 0.00 ! Y001 , from CG2O1 CG2DC1 NG2S1 OG2D1, penalty= 4

END
RETURN



Thanks again for your help. I don't expect to need much from here, just hoping for some tips to get me in the right direction. I hope this discussion will also help other users down the road.

Last edited by mgleed; 02/10/15 04:57 AM.
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Unfortunately, there are substantial penalties; I would hesitate to go much further w/o careful consideration. A more serious effort involving QM calculations may be required.


Rick Venable
computational chemist


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