In explicit solvent, protonation state changes are attempted for every
residue (in random order) every ntcnstph steps, which means that
protonation state changes were attempted for every CYS residue. If the
protonation state never changed, then every attempt was rejected. This
means that the energy penalty was far too large to be overcome by the pH
adjustment (and that in this simulation, the CYS residues are highly
unlikely to be found in the deprotonated form).
A few things to check:
* Make sure that CYS residues are actually specified in the cpin file
* Run some short sample simulations at much higher pH values (keep
increasing solvph until you start to see CYS transitions).
You can also generally get a good idea of why protonation changes are
constantly rejected by looking at the local environment of the CYS residues
in the trajectory.
Good luck,
Jason
On Mon, Sep 23, 2024 at 4:13 AM Nikolay Kuzmich via AMBER <amber.ambermd.org>
wrote:
> Dear Amber users and developers,
>
> just wanted to ask you about one detail:
>
> I carried out constant pH MD in explicit solvent, ASP, GLU, HIS and CYS
> were included in the list of titratable residues (the former 3 were renamed
> in AS4, GL4 and HIP, accordingly) and pH was set to 7.35.
>
>
> cpinutil.py -igb 2 -resnames HIP AS4 GL4 CYS -p
> cpH_prot_RC_tip3p18oct_hmr.prmtop -op cpH_prot_RC_tip3p18oct_hmr_cpi.prmtop
> -o cpH_prot_RC_tip3p18oct_hmr.cpin
>
>
> the mdin file was:
>
> &cntrl
> imin = 0, nstlim = 125000000, dt = 0.004,
> irest = 1, ntx = 5, ig = -1,
> temp0 = 300.0, icnstph=2,
> ntcnstph=100, ntrelax=200, solvph=7.35,
> ntc = 2, ntf = 2,
> ntwx = 12500, ntwr = 12500, ntpr = 2500,
> cut = 9.0, iwrap = 1, saltcon=0.15,
> ntt =3, gamma_ln=2.0, ntb = 1, ntp = 0,
> nscm = 1000,
> ioutfm=1, ntxo=2,
> /
> I applied the HMR technique as well.
>
>
> Having performed analysis after 500ns, I found that the cysteines
> underwent no transition and remained all the time in SH state; then I
> carried out the simulation 80ns long at pH=8.5 and again no transitions of
> CYS into anion were observed. From literature it is known that one CYS can
> have unusually low side-chain pKa.
>
> I guess some additional work-around for cysteines should have been done...
>
> Can you please prompt me which one exactly?
>
> Kind regards
>
> Nick
>
> Computational chemistry and
> molecular modeling
>
> The Nancy and Stephen Grand Israel National Center for Personalized
> Medicine
> Weizmann Institute of Science
>
> M +972 52 7439671
> 234 Herzl Street, P.o. Box 26,
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>
>
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--
Jason M. Swails
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Received on Tue Sep 24 2024 - 10:00:02 PDT
