On the propensity of Asn-Gly-containing heptapeptides to form β\beta-turn structures : comparison between ab initio quantum mechanical calculations and Molecular Dynamics simulations

Both molecular mechanical and quantum mechanical calculations play an important role in describing the behavior and structure of molecules. In this work, we compare for the same peptide systems the results obtained from folding molecular dynamics simulations with previously reported results from quantum mechanical calculations. More specifically, three molecular dynamics simulations of 5 $\mu$s each in explicit water solvent were carried out for three Asn-Gly-containing heptapeptides, in order to study their folding and dynamics. Previous data, based on quantum mechanical calculations and the DFT methods have shown that these peptides adopt $\beta$-turn structures in aqueous solution, with type I' $\beta$-turn being the most preferred motif. The results from our analyses indicate that for the given system the two methods diverge in their predictions. The possibility of a force field-dependent deficiency is examined as a possible source of the observed discrepancy.Comment: In the supplementary information file figures S5, S6 and S7 the $\beta$-turn occupancies were wrong. They have been correcte

Order through Disorder: Hyper-Mobile C-Terminal Residues Stabilize the Folded State of a Helical Peptide. A Molecular Dynamics Study

Conventional wisdom has it that the presence of disordered regions in the three-dimensional structures of polypeptides not only does not contribute significantly to the thermodynamic stability of their folded state, but, on the contrary, that the presence of disorder leads to a decrease of the corresponding proteins' stability. We have performed extensive 3.4 µs long folding simulations (in explicit solvent and with full electrostatics) of an undecamer peptide of experimentally known helical structure, both with and without its disordered (four residue long) C-terminal tail. Our simulations clearly indicate that the presence of the apparently disordered (in structural terms) C-terminal tail, increases the thermodynamic stability of the peptide's folded (helical) state. These results show that at least for the case of relatively short peptides, the interplay between thermodynamic stability and the apparent structural stability can be rather subtle, with even disordered regions contributing significantly to the stability of the folded state. Our results have clear implications for the understanding of peptide energetics and the design of foldable peptides

Folding Molecular Dynamics Simulations Accurately Predict the Effect of Mutations on the Stability and Structure of a Vammin-Derived Peptide

Folding molecular dynamics simulations amounting to a grand total of 4 μs of simulation time were performed on two peptides (with native and mutated sequences) derived from loop 3 of the vammin protein and the results compared with the experimentally known peptide stabilities and structures. The simulations faithfully and accurately reproduce the major experimental findings and show that (a) the native peptide is mostly disordered in solution, (b) the mutant peptide has a well-defined and stable structure, and (c) the structure of the mutant is an irregular β-hairpin with a non-glycine β-bulge, in excellent agreement with the peptide’s known NMR structure. Additionally, the simulations also predict the presence of a very small β-hairpin-like population for the native peptide but surprisingly indicate that this population is structurally more similar to the structure of the native peptide as observed in the vammin protein than to the NMR structure of the isolated mutant peptide. We conclude that, at least for the given system, force field, and simulation protocol, folding molecular dynamics simulations appear to be successful in reproducing the experimentally accessible physical reality to a satisfactory level of detail and accuracy

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

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

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

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

Folding Simulations of a Nuclear Receptor Box-Containing Peptide Demonstrate the Structural Persistence of the LxxLL Motif Even in the Absence of Its Cognate Receptor

Regulation of nuclear receptors by their coactivators involves the recognition and binding of a specific sequence motif contained in the coactivator sequence. This motif is known as the nuclear receptor (NR) box and contains a conserved LxxLL subsequence, where L is leucine and x is any amino acid residue. Crystallographic studies have shown that the LxxLL motifs adopt an α-helical conformation when bound to their cognate nuclear receptors. Here we use an extensive set of folding molecular dynamics simulations to examine whether the α-helical conformation demonstrated by the LxxLL motifs in the bound state may represent a persistent structural preference of these peptides even in the absence of their cognate receptors. To this end, we have performed a grand total of 35 μs of adaptive tempering folding simulations of an NR-box-containing peptide derived from Drosophila’s <i>fushi tarazu</i> segmentation gene product. Our simulationsperformed using full electrostatics and an explicit representation of two different solvents (water and a TFE/water mixture)clearly indicate the presence of a persistent helical preference of the LxxLL motif with a concomitant native-like structure and contacts between the motif’s leucine residues. To lend further support to our findings, we compare the simulation-derived peptide dynamics with experimental NMR-derived nuclear Overhauser effect (NOE) measurements that had been previously obtained for the same peptide in the same two solvents. The comparison demonstrates a quantitative agreement between simulation and experiment with average upper bound NOE violations of less than 0.084 Å, thus independently validating our main conclusion concerning the intrinsic preference of NR-box motifs to form helical structures even in the absence of their cognate receptors