Intrinsic Conformational Dynamics of Glycine and Alanine in Polarizable Molecular Dynamics Force Fields: Comparison to Spectroscopic Data

Molecular dynamics (MD) is a great tool for elucidating
conformational
dynamics of proteins and peptides in water at the atomistic level
that often surpasses the level of detail available experimentally.
Structure predictions, however, are limited by the accuracy of the
underlying MD force field. This limitation is particularly stark in
the case of intrinsically disordered peptides and proteins, which
are characterized by solvent-accessible and disordered peptide regions
and domains. Recent studies show that most additive MD force fields,
including CHARMM36m, do not reproduce the intrinsic conformational
distributions of guest amino acid residues x in cationic GxG peptides
in water in line with experimental data. Positing that a lack of polarizability
in additive MD force fields may be the culprit for the reported discrepancies,
we here examine the conformational dynamics of guest glycine and alanine
residues in cationic GxG peptides in water using two polarizable MD
force fields, CHARMM Drude and AMOEBA. Our results indicate that while
AMOEBA captures the experimental data better than CHARMM Drude, neither
of the two polarizable force fields offers an improvement of the Ramachandran
distributions of glycine and alanine residues in cationic GGG and
GAG peptides, respectively, over CHARMM36m.