Structural Transitions in the Polyalanine α-Helix under Uniaxial Strain

Ireta, Joel; Neugebauer, Jörg; Scheffler, Matthias; Rojo, and Arturo; Galván, Marcelo

doi:10.1021/ja053538j

Cited by 24 publications

(49 citation statements)

References 33 publications

(57 reference statements)

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“…We choose polyalanine as a target for our study due to its high propensity to form helical structures [11], and its widespread use as a benchmark system for peptide stability in experiment [12][13][14][15] and in theory (see, e.g., Refs. [16][17][18][19][20][21][22][23][24] and references therein). As detailed below, we find that vdW interactions stabilize native gas-phase helical forms of alanine polypeptide by a factor of 2 in relative energy over the fully extended structure on top of the widely used and established Perdew-Burke-Ernzerhof (PBE) [25] density functional.…”

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confidence: 99%

“…To quantify each contribution, we monitor the energy to add one amino acid residue to a finite polyalanine chain, E Ala ðnÞ ¼ E tot ðAla n Þ À E tot ðAla nÀ1 Þ, as a function of chain length n [20,21] in Fig. 1.…”

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confidence: 99%

“…1. The Ala n chain is frozen at the geometry of a hypothetical, infinite periodic helix [20,21]. This allows us to monitor the stabilization of the -helical motif towards the well-defined limit of a perfect infinite alpha helix, and to compare to the direct periodic calculations below.…”

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Unraveling the Stability of Polypeptide Helices: Critical Role of van der Waals Interactions

et al. 2011

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Folding and unfolding processes are important for the functional capability of polypeptides and proteins. In contrast with a physiological environment (solvated or condensed phases), an in vacuo study provides well-defined ''clean room'' conditions to analyze the intramolecular interactions that largely control the structure, stability, and folding or unfolding dynamics. Here we show that a proper consideration of van der Waals (vdW) dispersion forces in density-functional theory (DFT) is essential, and a recently developed DFT þ vdW approach enables long time-scale ab initio molecular dynamics simulations at an accuracy close to ''gold standard'' quantum-chemical calculations. The results show that the inclusion of vdW interactions qualitatively changes the conformational landscape of alanine polypeptides, and greatly enhances the thermal stability of helical structures, in agreement with gas-phase experiments. The helical motif is a ubiquitous conformation of amino acids in protein structures, and helix formation is a fundamental step of the protein folding process [1][2][3]. Simulations of helix formation and stability are typically carried out in solvent or condensed phases using classical, empirical ''force fields.'' However, different force field parameterizations lead to reliable results only for a narrow class of systems and conditions. A truly bottom-up understanding of polypeptide structure and dynamics would greatly benefit from a first-principles quantum-mechanical treatment, as it becomes increasingly more feasible for large systems and long time scales. In particular, quantum-mechanical simulations in vacuo are invaluable for a quantitative understanding of the intramolecular forces that largely control the structure, stability and (un) folding dynamics of polypeptides.Recent progress in the experimental isolation and spectroscopies of gas-phase biological molecules has lead to increasingly refined vibrational spectra for the structure of peptides and proteins [4][5][6]. In fact, in vacuo proteins frequently preserve the secondary structure (helices and sheets) observed in solution, and recent results [7] have shown that even tertiary and quaternary structures can be transferred into the gas phase. Joint experimental and ab initio theoretical studies can now successfully determine the geometries of small gas-phase peptides [8][9][10]. Nevertheless, many fundamental questions remain open, such as: (1) How stable is the folded polypeptide helix in comparison to other (meta)-stable structures? (2) How important are the different enthalpic and entropic contributions to the stability of helical conformations? Here we provide quantitative insight into the above two questions from first principles for the fundamental case of polyalanine helices in vacuo. Our study reveals the crucial role that van der Waals (vdW) interactions play for the helix stability and dynamics, illustrating how entropy is significantly altered as well. We choose polyalanine as a target for our study due to its high propensity to fo...

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Unraveling the Stability of Polypeptide Helices: Critical Role of van der Waals Interactions

et al. 2011

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“…To probe the (non)-locality of the formation of the clusters in rotational space, we modelled hydrogen bonds between backbone peptide units by Density Function Theory (DFT), which has proven to be successful in describing basic secondary structure motifs 18,19 . We first probe the energy landscape of rotational space by modelling two peptide units as described under Methods.…”

Section: Article Nature Communications | Doi: 101038/ncomms6803mentioning

confidence: 99%

“…Exchange-correlation effects were described using the Perdew-Burke-Ernzerhof (PBE) functional. This functional has been proven successful in describing the hydrogen binding within, for example, helical polypeptides (including the transitions from the alpha-helix to the pi-and 3-10 helices) 18 and in describing the side-group propensities within beta-sheets 19 .…”

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Hydrogen bond rotations as a uniform structural tool for analyzing protein architecture

et al. 2014

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Proteins fold into three-dimensional structures, which determine their diverse functions. The conformation of the backbone of each structure is locally at each C a effectively described by conformational angles resulting in Ramachandran plots. These, however, do not describe the conformations around hydrogen bonds, which can be non-local along the backbone and are of major importance for protein structure. Here, we introduce the spatial rotation between hydrogen bonded peptide planes as a new descriptor for protein structure locally around a hydrogen bond. Strikingly, this rotational descriptor sampled over high-quality structures from the protein data base (PDB) concentrates into 30 localized clusters, some of which correlate to the common secondary structures and others to more special motifs, yet generally providing a unifying systematic classification of local structure around protein hydrogen bonds. It further provides a uniform vocabulary for comparison of protein structure near hydrogen bonds even between bonds in different proteins without alignment.

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Conformational preferences of a short Aib/Ala‐based water‐soluble peptide as a function of temperature

2009

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The amino acid Aib predisposes a peptide to be helical with context-dependent preference for either 3(10)- or alpha- or a mixed helical conformation. Short peptides also show an inherent tendency to be unfolded. To characterize helical and unfolded states adopted by water-soluble Aib-containing peptides, the conformational preference of Ac-Ala-Aib-Ala-Lys-Ala-Aib-Lys-Ala-Lys-Ala-Aib-Tyr-NH(2) was determined by CD, NMR and MD simulations as a function of temperature. Temperature-dependent CD data indicated the contribution of two major components, each an admixture of helical and extended/polyproline II structures. Both right- and left-handed helical conformations were detected from deconvolution of CD data and (13)C NMR experiments. The presence of a helical backbone, more pronounced at the N-terminal, and a temperature-induced shift in alpha-helix/3(10)-helix equilibrium, more pronounced at the C-terminal, emerged from NMR data. Starting from polyproline II, the N-terminal of the peptide folded into a helical backbone in MD simulations within 5 ns at 60 degrees C. Longer simulations showed a mixed-helical backbone to be stable over the entire peptide at 5 degrees C while at 60 degrees C the mixed-helix was either stable at the N-terminus or occurred in short stretches through out the peptide, along with a significant population of polyproline II. Our results point towards conformational heterogeneity of water-soluble Aib-based peptide helices and the associated subtleties. The problem of analyzing CD and NMR data of both left- and right-handed helices are discussed, especially the validity of the ellipticity ratio [theta](222)/[theta](207), as a reporter of alpha-/3(10)- population ratio, in right- and left-handed helical mixtures.

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Structural Transitions in the Polyalanine α-Helix under Uniaxial Strain

Cited by 24 publications

References 33 publications

Unraveling the Stability of Polypeptide Helices: Critical Role of van der Waals Interactions

Unraveling the Stability of Polypeptide Helices: Critical Role of van der Waals Interactions

Hydrogen bond rotations as a uniform structural tool for analyzing protein architecture

Conformational preferences of a short Aib/Ala‐based water‐soluble peptide as a function of temperature

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