Multidimensional Mass Spectrometry of Synthetic Polymers and Advanced Materials

Multidimensional mass spectrometry interfaces a suitable ionization technique and mass analysis (MS) with fragmentation by tandem mass spectrometry (MS2) and an orthogonal online separation method. Separation choices include liquid chromatography (LC) and ion‐mobility spectrometry (IMS), in which separation takes place pre‐ionization in the solution state or post‐ionization in the gas phase, respectively. The MS step provides elemental composition information, while MS2 exploits differences in the bond stabilities of a polymer, yielding connectivity and sequence information. LC conditions can be tuned to separate by polarity, end‐group functionality, or hydrodynamic volume, whereas IMS adds selectivity by macromolecular shape and architecture. This Minireview discusses how selected combinations of the MS, MS2, LC, and IMS dimensions can be applied, together with the appropriate ionization method, to determine the constituents, structures, end groups, sequences, and architectures of a wide variety of homo‐ and copolymeric materials, including multicomponent blends, supramolecular assemblies, novel hybrid materials, and large cross‐linked or nonionizable polymers.More dimensions for MS: Multidimensional mass spectrometry combines mass analysis with tandem mass spectrometry fragmentation and an orthogonal separation method, such as liquid chromatography (LC) fractionation or ion‐mobility spectrometry (IMS), to achieve top‐down characterization of the composition, end groups, connectivity, and architecture of synthetic materials. CCS=collision cross‐section; CE=collision energy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137445/1/anie201607003.pd

The Sodium Ion Affinities of Simple Di-, Tri-, and Tetrapeptides

The sodium ion affinities (binding energies) of nineteen peptides containing 2-4 residues have been determined by experimental and computational approaches. Na+-bound heterodimers with amino acid and peptide ligands (Pep1, Pep2) were produced by electrospray ionization. The dissociations of these Pep1–Na+–Pep2 ions to Pep1–Na+ and Pep2–Na+ were examined by collisionally activated dissociation to construct a ladder of relative affinities via the kinetic method. The accuracy of this ladder was subsequently ascertained by experiments using several excitation energies for four peptide pairs. The relative scale was converted to absolute affinities by anchoring the relative values to the known Na+ affinity of GlyGly. The Na+ affinities of AlaAla, HisGly, GlyHis, GlyGlyGly, AlaAlaAla, GlyGlyGlyGly, and AlaAlaAlaAla were also calculated at the MP2(full)/6-311 + G(2d,2p) level of ab initio theory using geometries that were optimized at the MP2(full)/6-31G(d) level for AlaAla or HF/6-31G(d) level for the other peptides; the resulting values agree well with experimental Na+ affinities. Increasing the peptide size is found to dramatically augment the Na+ binding energy. The calculations show that in nearly all cases, all available carbonyl oxygens are sodium binding sites in the most stable structures. Whenever side chains are available, as in HisGly and GlyHis, specific additional binding sites are provided to the cation. Oligoglycines and oligoalanines have similar binding modes for the di- and tripeptides, but differ significantly for the tetrapeptides: while the lowest energy structure of GlyGlyGlyGly–Na+ has the peptide folded around the ion with all four carbonyl oxygens in close contact with Na+, that of AlaAlaAlaAla–Na+ involves a pseudo-cyclic peptide in which the C and N termini interact via hydrogen bonding, while Na+ sits on top of the oxygens of three nearly parallel C=O bonds

Self-assembly of polyoxometalate-peptide hybrids in solution: elucidating the contributions of multiple possible driving forces

Incorporating the building blocks of nature (e.g., peptides and DNA) into inorganic polyoxometalate (POM) clusters is a promising approach to improve the compatibilities of POMs in biological fields. To extend their biological applications, it is necessary to understand the importance of different non‐covalent interactions during self‐organization. A series of Anderson POM–peptide hybrids have been used as a simple model to demonstrate the role of different interactions in POM–peptide (biomolecules) systems. Regardless of peptide chain length, these hybrids follow similar solution behaviors, forming hollow, spherical supramolecular structures in acetonitrile/water mixed solvents. The incorporation of peptide tails introduces interesting stimuli‐responsive properties to temperature, hybrid concentration, solvent polarity and ionic strength. Unlike the typical bilayer amphiphilic vesicles, they are found to follow the blackberry‐type assemblies of hydrophilic macroions, which are regulated by electrostatic interaction and hydrogen bonding. The formation of electrostatic assemblies before the supramolecular formation is confirmed by ion‐mobility mass spectrometry (IMS‐MS)

Trehalose Glycopolymer Enhances Both Solution Stability and Pharmacokinetics of a Therapeutic Protein

Biocompatible polymers such as poly(ethylene glycol) (PEG) have been successfully conjugated to therapeutic proteins to enhance their pharmacokinetics. However, many of these polymers, including PEG, only improve the in vivo lifetimes and do not protect proteins against inactivation during storage and transportation. Herein, we report a polymer with trehalose side chains (PolyProtek) that is capable of improving both the external stability and the in vivo plasma half-life of a therapeutic protein. Insulin was employed as a model biologic, and high performance liquid chromatography and dynamic light scattering confirmed that addition of trehalose glycopolymer as an excipient or covalent conjugation prevented thermal or agitation-induced aggregation of insulin. The insulin-trehalose glycopolymer conjugate also showed significantly prolonged plasma circulation time in mice, similar to the analogous insulin-PEG conjugate. The insulin-trehalose glycopolymer conjugate was active as tested by insulin tolerance tests in mice and retained bioactivity even after exposure to high temperatures. The trehalose glycopolymer was shown to be non-toxic to mice up to at least 1.6 mg/kg dosage. These results together suggest that the trehalose glycopolymer should be further explored as an alternative to PEG for long circulating protein therapeutics

Characterization of the C3H6O+. ion from 2-methoxyethanol. Mixture analysis by dissociation and neutralization—reionization

The C3H6O+. ion formed upon the dissociative ionization of 2-methoxyethanol is identified by a combination of several tandem mass spectrometry methods, including metastable ion (MI) characteristics, collisionally activated dissociation (CAD), and neutralization—reionization mass spectrometry (NRMS). The experimental data conclusively show that 2-methoxyethanol molecular ion, namely, HOCH2CH2OCH3+., loses H2O to yield mainly the distonic radical ion ·CH2CH2OCH2+ along with a smaller amount of ionized methyl vinyl ether, namely, CH2=CHOCH3+.. Ring-closed products, such as the oxetane or the propylene oxide ion are not observed. The proportion of ·CH2CH2OCH2+ increases with decreasing internal energy of the 2-methoxyethanol ion, which indicates a lower critical energy for the pathway leading to this product than for the competitive generation of CH2=CHOCH3+.. The present study also uses MI, CAD, and NRMS data to assess the structure of the distonic ion+ (CH3)CHOCH2 · (ring-opened ionized propylene oxide) and evaluate its isomerization proclivity toward the methyl vinyl ether ion

The sodium ion affinities of asparagine, glutamine, histidine and arginine

International audienceThe sodium ion affinities of the amino acids Asn, Gln, His and Arg have been determined by experimental and computational approaches (for Asn, His and Arg). Ne-bound heterodimers with amino acid and peptide ligands (Pep(1), Pep(2)) were produced by electrospray ionization. From the dissociation kinetics of these Pep(1)-Na+-Pep(2) ions to Pep(1)-Na+ and Pep(2)-Na+, determined by collisionally activated dissociation, a ladder of relative affinities was constructed and subsequently converted to absolute affinities by anchoring the relative values to known Na+ affinities. The Na+ affinities of Asn, His and Arg, were calculated at the MP2(full)/6-311+G(2d,2p)//MP2/6-31G(d) level of ab initio theory. The resulting experimental and computed Na+ affinities are in excellent agreement with one another. These results, combined with those of our previous studies, yield the sodium ion affinities of 18 out of the 20 alpha-amino acids naturally occurring in peptides and proteins of living systems

Cu(II)-catalyzed reactions in ternary [Cu(AA)(AA - H)]+ complexes (AA = Gly, Ala, Val, Leu, Ile, t-Leu, Phe).

International audienceThe unimolecular chemistry of [Cu(II)AA(AA - H)](+) complexes, composed of an intact and a deprotonated amino acid (AA) ligand, have been probed in the gas phase by tandem and multistage mass spectrometry in an electrospray ionization quadrupole ion trap mass spectrometer. The amino acids examined include Gly, Ala, Val, Leu, Ile, t-Leu and Phe. Upon collisionally-activated dissociation (CAD), the [Cu(II)AA(AA - H)](+) complexes undergo decarboxylation with simultaneous reduction of Cu(II) to Cu(I); during this process, a radical site is created at the alpha-carbon of the decarboxylated ligand (H(2)N(1) - (*)C(alpha)H - C(beta)H(2) - R; R = side chain substituent). The radical site is able to move along the backbone of the decarboxylated amino acid to form two new radicals (HN(1)(*) - C(alpha)H(2) - C(beta)H(2) - R and H(2)N(1) - C(alpha)H(2) - (*)C(beta)H - R). From the complexes of Gly and t-Leu, only C(alpha) and N(1) radicals can be formed. The whole radical ligand can be lost to form [Cu(I)AA](+) from these three isomeric radicals. Alternatively, further radical induced dissociations can take place along the backbone of the decarboxylated amino acid ligand to yield [Cu(II)AA(AA - 2H - CO(2))](+), [Cu(I)AA((*)NH(2))](+), [Cu(I)AA(HN = C(alpha)H(2))](+), or [Cu(I)AA(H(2)N - C(alpha)H = C(beta)H - R'](+) (R' = partial side chain substituent). The sodiated copper complexes, [Cu(II)(AA - H + Na)(AA - H)](+), show the same fragmentation patterns as their non-sodiated counterparts; sodium ion is retained on the intact amino acid ligand and is not involved in the CAD pathways. The amino groups of both AA units, the carbonyl group of the intact amino acid, and the deprotonated hydroxyl oxygen coordinate Cu(II) in square-planar fashion. Ab initio calculations indicate that the metal ion facilitates hydrogen atom shuttling between the N(1), C(alpha) and C(beta) atoms of the decarboxylated amino acid ligand. The dissociations of the decarboxylated radical ions unveil important insight about the so far largely unknown intrinsic chemistry of alpha-amino acid and peptide radicals, which are implicated as intermediates in numerous pathogenic biological processes