On the Foldability of Tryptophan-Containing Tetra-
and Pentapeptides: An Exhaustive Molecular Dynamics Study
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Abstract
Short
peptides serve as minimal model systems to decipher the determinants
of foldability due to their simplicity arising from their smaller
size, their ability to echo protein-like structural characteristics,
and their direct implication in force field validation. Here, we describe
an effort to identify small peptides that can still form stable structures
in aqueous solutions. We followed the <i>in silico</i> folding
of a selected set of 8640 tryptophan-containing tetra- and pentapeptides
through 15 210 molecular dynamics simulations amounting to
a total of 272.46 μs using explicit representation of the solute
and full treatment of the electrostatics. The evaluation and sorting
of peptides is achieved through scoring functions, which include terms
based on interatomic vector distances, atomic fluctuations, and rmsd
matrices between successive frames of a trajectory. Highly scored
peptides are studied further via successive simulation rounds of increasing
simulation length and using different empirical force fields. Our
method suggested only a handful of peptides with strong foldability
prognosis. The discrepancies between the predictions of the various
force fields for such short sequences are also extensively discussed.
We conclude that the vast majority of such short peptides do not adopt
significantly stable structures in water solutions, at least based
on our computational predictions. The present work can be utilized
in the rational design and engineering of bioactive peptides with
desired molecular properties