Self‐association and solubility of peptides: Solvent‐titration study of N^α‐protected C‐terminal sequences of substance P

Abstract

SynopsisSelf-association of Na-protected peptides related to Cterminal sequences of substance P in methylene chloride was disrupted by adding increasing amounts of various polar organic solvents. This process was monitored by the disappearance of the amide I C=O stretching band (1630 cm-I ) of strongly intermolecularly H-bonded molecules in the irabsorption spectra. The effects induced by mainchain length, incorporation at position 9 of a residue promoting folding (a-aminoisobutyric acid), the nature of solvent, and peptide concentration were established. A corollary IH-nmr investigation provided detailed information on the NH protons involved in the self-association process as Hbonding donors. The increasing propensity to aggregate exhibited by these peptides is paralleled by a decrease in their solubility. The impact of these results on the synthesis of substance P short sequences is briefly outlined.'This is part 136 of the Linear Oligopeptides series. For part 135, see Bismara,

Proline N-oxides: modulators of the 3D conformation of linear peptides through “NO-turns”

“…When −Δδ/ΔT < 3 ppb K −1 the amide proton is shielded from the solvent, due to hydrogen bonding with any carbonyl oxygen atom. [91][92][93][94][95][96] The plotted −Δδ/ΔT graphs (available in the ESI ‡) for peptides and N-methylated peptides in DMSO-d 6 confirmed that no intramolecular hydrogen bonds exist for peptides 1a-4a. The presence of hydrogen bonds between the NO moiety and hydrogen-bonded NH in different N-oxide peptides 1b-4b was also investigated with this method.…”

“…Furthermore, an analysis of the thermal behaviour of hydrogen bonds in the peptides by NMR is an elegant technique to study the exact nature of this interaction. [91][92][93][94][95][96] Normally the intramolecular hydrogen bonding interaction between a hydrogen bond donor (amide proton) and an acceptor (carbonyl oxygen) in a peptide is disturbed at higher temperatures; the amide proton signals also experience a downfield shift (less through space deshielding) in the 1 H NMR spectra in aprotic solvent systems. [91][92][93][94][95][96] In aprotic solvents such as DMSO-d 6 , when −Δδ/ΔT > 5 1 ppb K −1 , the typical intramolecular peptide hydrogen bonding is absent if the amide protons are solvent-exposed.…”

N‐Acylureas in Peptide Synthesis: An X‐Ray Diffraction and IR‐Absorption Study

“…-A very useful probe to determine the onset of strong N-H. . .O=C H-bonds in peptides, as those typical of an intermolecular B-sheet structure and responsible for the low solubility of peptides in solvents of low polarity [14][15][16][17][18][19][20][21][22][23], is represented by the IR absorption band near 1630 cm-' assigned to the C=O stretching mode [4346]. Since in actual peptide synthesis only a small portion of the carboxyl component is converted to N-acylurea, the conclusion can be drawn that this side product should cause only a minor effect on the self-association properties of peptide chains.…”

Membrane Structure of Substance P. III. Secondary Structure of Substance P in 2,2,2‐Trifluoroethanol, Methanol, and on Flat Lipid Membranes Studied by Infrared Spectroscopy

“…In our peptides, both are present (1-3, [Leu9]-3 and [Leu9]-l even contain prolines). The lack of the N-terminal charge may have caused the tendency of Boc-6 to aggregate to /?-structures in CH,Cl, solution containing only small amounts of DMSO [6]. We therefore assume, in a first approximation, predominantly monomeric species in our CF,CH,OH solutions.…”

“…Furthermore, its CD spectrum is time-dependent [3]. These studies were complemented by an IR investigation of the self-association of N(a)-protected C-terminal segments of 1 in mixtures of CH,C12 and DMSO [6]. Solventtitration studies of the 'H-NMR spectrum of Boc-Phe-Phe-Gly-Leu-Met-NH, revealed that the amide protons of Phe-7, Phe-8, Met-I I, and one proton of the primary amide group are strongly solvent-dependent, whereas the amide groups of Gly-9, Leu-10, and one proton of the primary amide group show reduced solvent accessibility (residue numbering of 1).…”