there could be lots of things going on with the force field and water
model, but I would start by thinking about what you mean when you say "
tighter association than experimentally observed". The experiment would
most likely involve some measure of equilibrium constant, and to compare to
that you would need to see many events where the peptide reversible
contacts the protein and then dissociates, as with a small molecule
equilibrium process. That would be very challenging to simulate with any
statistical reliability. Certainly seeing it move to the protein surface
could be consistent with experiments if there is any binding affinity at
all - but also could be inconsistent and the association might be too
strong. You really can't say much from your current data.
but again, it could well be an issue with the computational models. there
are definitely articles in the literature describing over-stabilization of
compact structures, particularly notable for simulations of IDPs. I think
it's an area of active research since (1) experimental data have been
scarce and (2) generating a reliable distribution of these unfolded
structures is typically too costly to achieve.
On Wed, Mar 13, 2024 at 10:56 AM Sasha Buzko via AMBER <amber.ambermd.org>
wrote:
> Dear All,
>
> I'm running explicit solvent simulations of a globular protein with a long
> linker connected to a helical peptide. The linker is a long CYX-bound
> non-peptide with a PEG-amide type of structure. I use ff19SB with OPC water
> model, add ions to ~0.15 mM level and to neutralize the system.
>
> The equilibration runs fine but then I see an overall drift of the
> connected peptide to the carrier protein. It's basically trying to fold
> into the protein.
>
>
>
> As a control, I ran 1qm9 (solution NMR structure), which has two loosely
> associated subdomains connected with a peptide linker. After 200 ns, the
> subdomains came much closer to each other and the linker remained solvated.
> In other words, there is tighter association than experimentally observed.
>
> Not sure how much the non-peptide nature of my linker is impacting this.
>
>
>
> I'm wondering how much of it is real and how much is due to underestimated
> solvation. Does anyone have experience modeling these types of
> solvent-exposed structures? Do you think I've hit the limits of the force
> field or am I missing something?
>
>
>
>
>
> Thank you in advance!
>
>
>
> Sasha
>
>
>
>
> ---
> Oleksandr "Sasha" Buzko
> Computational Biology
> ImmunityBio
> 9922 Jefferson Blvd
> Culver City, CA 90230
>
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Received on Wed Mar 13 2024 - 10:00:02 PDT
