On the Foldability of Tryptophan-Containing Tetra- and Pentapeptides: An Exhaustive Molecular Dynamics Study

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 in silico 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.

Molecular simulations of self-assembling bio-inspired supramolecular systems and their connection to experiments

“…An exhaustive set of MD simulations on the folding of tetra- and pentapeptides, performed using CHARMM, AMBER, as well as OPLS, showed clear inconsistencies between these force fields. 26 A similar observation was made in a study on the dimerization propensity of amino acid side chain residues. 27 …”

Exploring the sequence space for (tri-)peptide self-assembly to design and discover new hydrogels

“…However, it is clear that depending on the desired properties of the self-assembling peptide, new filters can be developed. Automated screening based on the shape of the nanostructure 52 , peptide foldability 53 , the presence of certain amino-acid interactions or other molecular properties could be equally useful and constitute future directions for this research.…”

The membrane-active amphibian peptide caerin 1.8 inhibits fibril formation of amyloid β1-42

“…This system was then used for all unrestrained molecular dynamics (MD) simulations which were carried out using the SANDER module. The AMBER structure in the water box was heated to 325K over 50 ps to avoid being kinetically trapped in local minima and then subjected to unrestrained MD simulations at 325K for the purpose of complex equilibration [12,14,34]. MD simulation was continued until the root mean square deviation (RMSD) was ≤ 3Å.…”

“…Some truncated forms of caerin 1.8 also inhibit fibril formation of A42. For example, caerin 1.8 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) [ 1 GLFKVLGSV 10 AKHL(NH2) and caerin 1.8 (22)(23)(24)(25) [KVLGSV 10 AKHLLPHVVP 20 VIAEKL(NH2)] show 85% and 75% respectively of the inhibition activity of the parent caerin 1.8. The synthetic peptide KLVFFKKKKKK is a known inhibitor of A42 fibril formation, and was used as a standard in this study.…”