Dear Amber community,
for my PhD project I am working on covalent ligand MD simulations.
Currently I am trying to figure out, what the best way of modeling such
a system is. I believe there are two general approaches:
1. use a protein force field (e.g. ff19SB) for the protein, GAFF2 for
the ligand and derive custom parameters for the junction (an frcmod file
with parameters for mixed atom types). Create the bond in leap.
2. define a modified amino acid in a prepi/library file and patch it
into the backbone of the protein. Thereby the whole adduct would be
described by GAFF2 and one would need to define parameters at the
junction to the protein backbone.
I want to use QM+RESP to derive the single point charges for the ligand.
I would argue that the second approach might be more accurate for charge
derivation, and also less sensitive to custom parameters, as the
backbone is more rigid than the side chain. I would validate that GAFF2
can produce accurate backbone terms, of course.
Given a prepi file of the capped (NME/ACE) amino acid-ligand adduct, I
can manually change the backbone atoms to use ff19SB atom types and then
use parmchk2 to fill missing parameters for the mixed atom types with
GAFF2 analogies. Thereby I have created an frcmod file containing
junction parameters. I can also define a new atom type in chemical
analogy to CX for the alpha carbon of this adduct, in order to prevent
the frcmod from overwriting standard parameters for the whole protein.
The adducts I want to simulate are cysteines covalently bound to
acrylamides, like pdb code 6oim for example. Does this approach seem
sensible to you, or am I missing something obvious? I don’t just want
working parameters but really investigate parametrisation for covalent
ligands. Any experiences, references, or example workflows would be
extremely helpful.
Thank you so much!
Jefta Wucherpfennig – Universität Würzburg
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Received on Thu Feb 19 2026 - 05:00:02 PST
