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Issue 11, 2015
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Exploring the conformational preferences of 20-residue peptides in isolation: Ac-Ala19-Lys + H+vs. Ac-Lys-Ala19 + H+ and the current reach of DFT

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Abstract

Reliable, quantitative predictions of the structure of peptides based on their amino-acid sequence information are an ongoing challenge. We here explore the energy landscapes of two unsolvated 20-residue peptides that result from a shift of the position of one amino acid in otherwise the same sequence. Our main goal is to assess the performance of current state-of-the-art density-functional theory for predicting the structure of such large and complex systems, where weak interactions such as dispersion or hydrogen bonds play a crucial role. For validation of the theoretical results, we employ experimental gas-phase ion mobility-mass spectrometry and IR spectroscopy. While unsolvated Ac-Ala19-Lys + H+ will be shown to be a clear helix seeker, the structure space of Ac-Lys-Ala19 + H+ is more complicated. Our first-principles structure-screening strategy using the dispersion-corrected PBE functional (PBE + vdWTS) identifies six distinctly different structure types competing in the low-energy regime (≈16 kJ mol−1). For these structure types, we analyze the influence of the PBE and the hybrid PBE0 functional coupled with either a pairwise dispersion correction (PBE + vdWTS, PBE0 + vdWTS) or a many-body dispersion correction (PBE + MBD*, PBE0 + MBD*). We also take harmonic vibrational and rotational free energy into account. Including this, the PBE0 + MBD* functional predicts only one unique conformer to be present at 300 K. We show that this scenario is consistent with both experiments.

Graphical abstract: Exploring the conformational preferences of 20-residue peptides in isolation: Ac-Ala19-Lys + H+vs. Ac-Lys-Ala19 + H+ and the current reach of DFT

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Publication details

The article was received on 28 Nov 2014, accepted on 11 Feb 2015 and first published on 12 Feb 2015


Article type: Paper
DOI: 10.1039/C4CP05541A
Citation: Phys. Chem. Chem. Phys., 2015,17, 7373-7385
  • Open access: Creative Commons BY license
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    Exploring the conformational preferences of 20-residue peptides in isolation: Ac-Ala19-Lys + H+vs. Ac-Lys-Ala19 + H+ and the current reach of DFT

    F. Schubert, M. Rossi, C. Baldauf, K. Pagel, S. Warnke, G. von Helden, F. Filsinger, P. Kupser, G. Meijer, M. Salwiczek, B. Koksch, M. Scheffler and V. Blum, Phys. Chem. Chem. Phys., 2015, 17, 7373
    DOI: 10.1039/C4CP05541A

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