Abstract

We investigate the peptide AcPheAla5LysH+, a model system for studying helix formation in the gas phase, in order to fully understand the forces that stabilize the helical structure. In particular, we address the question of whether the local fixation of the positive charge at the peptide's C-terminus is a prerequisite for forming helices by replacing the protonated C-terminal Lys residue by Ala and a sodium cation. The combination of gas-phase vibrational spectroscopy of cryogenically cooled ions with molecular simulations based on density-functional theory (DFT) allows for detailed structure elucidation. For sodiated AcPheAla6, we find globular rather than helical structures, as the mobile positive charge strongly interacts with the peptide backbone and disrupts secondary structure formation. Interestingly, the global minimum structure from simulation is not present in the experiment. We interpret that this is due to high barriers involved in rearranging the peptide-cation interaction that ultimately result in kinetically trapped structures being observed in the experiment.

Highlights

  • Helical secondary structural motifs, such as α and 310, are common in proteins.[1]

  • To investigate the importance of the charge fixed at the Cterminus, we focus on the well-studied system[8,16] of AcPheAla5LysH+ and compare it to AcPheAla6 + Na+ (Figure 1, parts b and c, respectively)

  • Even though four structures were successfully assigned to the experimental spectra, the question whether the search was complete and the whether these conformers are located in the global minimum region remained open

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Summary

Introduction

Helical secondary structural motifs, such as α and 310, are common in proteins.[1]. In solution, the helix propensity is determined both by intramolecular interactions and protein− solvent interaction. Pioneering ion-mobility experiments in the group of Jarrold[2,3] examined the role of N- and C-terminal residues on gas-phase helix formation for the sequences AlanH+, AcLysAlanH+, and AcAlanLysH+. They concluded that AlanH+ and AcLysAlanH+ adopt globular conformations in the gas phase independent of the length of the amino-acid chain while AcAlanLysH+ is helical for n > 8.14 The identities of these structures were confirmed by theoretical and experimental vibrational spectroscopy in the work of Rossi et al.[10] and Schubert et al.,[12] respectively.

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