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

Abstract

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.

Thermodynamic Basis for the Stabilization of Helical Peptoids by Chiral Sidechains

“…The potential of biomimetic foldamers to expand the regime of thermally accessible configurations has further been highlighted in a recent discovery by Mannige et al, which demonstrated the existence of a novel secondary structure motif possible through alternating backbone patterns (i.e., alternating primary motifs) stabilized by intermolecular interactions, leading to the discovery of a new aggregate macromolecular structure . However, previous computational studies have mainly focused on applying simulations to characterize entropic and enthalpic driving forces behind homopolymer assembly into singular known experimental structures such as the PPI-like helix, cyclic peptoids, or disordered sequences. − …”

Development of a Systematic and Extensible Force Field for Peptoids (STEPs)

“…It is worth noting that multiple force fields are available in the protein space, but that field is significantly more developed and studied. Despite this higher bar to entry, peptoid simulation papers include at least 19 GAFF-based, ,,− 13 MFTOID-, ,− 11 CHARMM-, or CGenFF-based, − 3 PEPDROID-based, − and other computational studies. − One particularly noteworthy effort was the development of a peptoid rotamer library containing over 50 side chains in the structural prediction tool ROSETTA based on CHARMM peptide parameters. , …”

On the Conformation of Anionic Peptoids in the Gas Phase

“…MD simulations revealed that strong charge/dipole interactions between the CO groups and the proton (ammonium group) induce the folding of the peptoid ions around the charge and the loss of the extended helical structure. In a second study, we introduced additional non-covalent interactions through H-bond donor groups (carboxylic acid moieties) carried by the pending side chains . Using the IMS–MS/MD approach, we detected helices in the gas phase cemented by the formation of an intra-residue H-bond network associating the hydrogen atom from the side chain carboxylic acid to the oxygen atom of the amide inside the same residue.…”

“…In a second study, we introduced additional non-covalent interactions through H-bond donor groups (carboxylic acid moieties) carried by the pending side chains. 43 Using the IMS−MS/MD approach, we detected helices in the gas phase cemented by the formation of an intra-residue H-bond network associating the hydrogen atom from the side chain carboxylic acid to the oxygen atom of the amide inside the same residue. We further demonstrated that the obtention of stable peptoid helices in the gas phase is conditioned by different factors: (i) the possibility to create a H-bond network; (ii) the presence of a sufficient amount of residues to energetically counterbalance the charge induced folding; and (iii) the presence of bulky side chains to rigidify the backbone (generate a high degree of steric hindrance).…”

“…We further demonstrated that the obtention of stable peptoid helices in the gas phase is conditioned by different factors: (i) the possibility to create a H-bond network; (ii) the presence of a sufficient amount of residues to energetically counterbalance the charge induced folding; and (iii) the presence of bulky side chains to rigidify the backbone (generate a high degree of steric hindrance). 43 In the present study, we want to assess whether helical peptoid ions can be stabilized in the gas phase using the "macrodipole approach", 44 successfully employed for the detection of helical peptides in the gas phase. Although helical in solutions, protonated poly(alanine) ions with up to 20 residues do not retain their shape in a vacuum-like environment since the charge destabilizes the helical conformation (Scheme 2).…”