Extending the Stochastic Titration CpHMD to CHARMM36m

The impact of pH on proteins is significant
but often neglected
in molecular dynamics simulations. Constant-pH Molecular Dynamics
(CpHMD) is the state-of-the-art methodology to deal with these effects.
However, it still lacks widespread adoption by the scientific community.
The stochastic titration CpHMD is one of such methods that, until
now, only supported the GROMOS force field family. Here, we extend
this method’s implementation to include the CHARMM36m force
field available in the GROMACS software package. We test this new
implementation with a diverse group of proteins, namely, lysozyme,
Staphylococcal nuclease, and human and E. coli thioredoxins.
All proteins were conformationally stable in the simulations, even
at extreme pH values. The RMSE values (pKa prediction vs experimental) obtained were very encouraging, in particular
for lysozyme and human thioredoxin. We have also identified a few
residues that challenged the CpHMD simulations, highlighting scenarios
where the method still needs improvement independently of the force
field. The CHARMM36m all-atom implementation was more computationally
efficient when compared with the GROMOS 54A7, taking advantage of
a shorter nonbonded interaction cutoff and a less frequent neighboring
list update. The new extension will allow the study of pH effects
in many systems for which this force field is particularly suited,
i.e., proteins, membrane proteins, lipid bilayers, and nucleic acids.