On the Conformation of Anionic Peptoids in the Gas Phase.

Although N-(S)-phenylethyl peptoids are known to adopt helical structures in solutions, the corresponding positively charged ions lose their helical structure during the transfer from the solution to the gas phase due to the so-called charge solvation effect. We, here, considered negatively charged peptoids to investigate by ion mobility spectrometry-mass spectrometry whether the structural changes described in the positive ionization mode can be circumvented in the negative mode by a fine-tuning of the peptoid sequence, that is, by positioning the negative charge at the positive side of the helical peptoid macrodipole. N-(S)-(1-carboxy-2-phenylethyl) (Nscp) and N-(S)-phenylethyl (Nspe) were selected as the negative charge carrier and as the helix inductor, respectively. We, here, report the results of a joint theoretical and experimental study demonstrating that the structures adopted by the NspenNscp anions remain compactly folded in the gas phase for chains containing up to 10 residues, whereas no evidence of the presence of a helical structure was obtained, even if, for selected sequences and lengths, different gas phase conformations are detected.

Helical Peptoid Ions in the Gas Phase: Thwarting the Charge Solvation Effect by H-Bond Compensation.

Folding and unfolding processes are key aspects that should be mastered for the design of foldamer molecules for targeted applications. In contrast to the solution phase, in vacuo conditions represent a well-defined environment to analyze the intramolecular interactions that largely control the folding/unfolding dynamics. Ion mobility mass spectrometry coupled to theoretical modeling represents an efficient method to decipher the spatial structures of gaseous ions, including foldamers. However, charge solvation typically compacts the ion structure in the absence of strong stabilizing secondary interactions. This is the case in peptoids that are synthetic peptide regioisomers whose side chains are connected to the nitrogen atoms of the backbone instead of α-carbon as in peptides, thus implying the absence of H-bonds among the core units of the backbone. A recent work indeed reported that helical peptoids based on Nspe units formed in solution do not retain their secondary structure when transferred to the gas phase upon electrospray ionization (ESI). In this context, we demonstrate here that the helical structure of peptoids bearing (S)-N-(1-carboxy-2-phenylethyl) bulky side chains (Nscp) is largely preserved in the gas phase by the creation of a hydrogen bond network, induced by the presence of carboxylic moieties, that compensates for the charge solvation process.

How Spherical Are Gaseous Low Charged Dendrimer Ions: A Molecular Dynamics/Ion Mobility Study?

The globular shape of gaseous ions, resulting from the ionization of large molecules such as polymers and proteins, is a recurring subject that has undergone a renewed interest with the advent of ion mobility spectrometry (IMS), especially in conjunction with theoretical chemistry techniques such as Molecular Dynamics (MD). Globular conformations result from a fine balance between entropy and enthalpy considerations. For multiply charged ions isolated in the gas phase of a mass spectrometer, the Coulombic repulsion between the different charges tends to prevent the ions from adopting a compact, and folded 3D structure. In the present paper, we closely associate data from IMS experiments and MD simulations to unambiguously access the conformations of dendrimer ions in the gas phase with special attention paid to the dendrimer structure, the generation, and the charge state. By doing so, we here combine a set of structural tools able to evaluate the (non)globular shape of ions based on both experimental and theoretical results.

Helicity of Peptoid Ions in the Gas Phase.

Peptoids are attractive substitutes for peptides in several research areas, especially when they adopt a helical structure. The chain-size evolution of the secondary structure of the widely studied (S)-N-1-phenylethyl peptoids is here analyzed by means of the ion mobility mass spectrometry technique increasingly used as a powerful analytical tool and is further supported by theoretical modeling. We conclude that the helical shape of the peptoids prevailing in solution is lost in the gas phase by the need to screen the positive charge borne by the peptoid even though the collisional cross sections are close to the values expected for helical systems. We further illustrate that trend line analyses predicting molecular shapes from fits of the size evolution of cross sections can be very misleading since they critically depend on the range of polymerization degrees under study.

Backbone Cleavages of Protonated Peptoids upon Collision-Induced Dissociation: Competitive and Consecutive B-Y and A1-YX Reactions.

Mass spectrometric techniques and more particularly collision-induced dissociation (CID) experiments represent a powerful method for the determination of the primary sequence of (bio)molecules. However, the knowledge of the ion fragmentation patterns say the dissociation reaction mechanisms is a prerequisite to reconstitute the sequence based on fragment ions. Previous papers proposed that protonated peptoids dissociate following an oxazolone-ring mechanism starting from the O-protonation species and leading to high mass Y sequence ions. Here we revisit this backbone cleavage mechanism by performing CID and ion mobility experiments, together with computational chemistry, on tailor-made peptoids. We demonstrated that the B/Y cleavages of collisionally activated O-protonated peptoids must involve the amide nitrogen protonated structures as the dissociating species, mimicking the CID behavior of protonated peptides. Upon the nucleophilic attack of the oxygen atom of the N-terminal adjacent carbonyl group on the carbonyl carbon atom of the protonated amide, the peptoid ions directly dissociate to form an ion-neutral complex associating an oxazolone ion to the neutral truncated peptoid residue. Dissociation of the ion/neutral complex predominantly produces Y ions due to the high proton affinity of the secondary amide function characteristic of truncated peptoids. Whereas the production of Yx ions from acetylated peptoids also involves the B/Y pathway, the observation of abundant Yx ions from non-acetylated peptoid ions is shown in the present study to arise from an A1-Yx mechanism. The consecutive and competitive characters of the A1-Yx and the B/Y mechanisms are also investigated by drift time-aligned CID experiments.