A growing number of approaches to “staple” α‐helical peptides into a bioactive conformation using cysteine cross‐linking are emerging. Here, the replacement of l‐cysteine with “cysteine analogues” in combinations of different stereochemistry, side chain length and beta‐carbon substitution, is explored to examine the influence that the thiol‐containing residue(s) has on target protein binding affinity in a well‐explored model system, p53–MDM2/MDMX, which is constituted by the interaction of the tumour suppressor protein p53 and proteins MDM2 and MDMX, which regulate p53 activity. In some cases, replacement of one or more l‐cysteine residues afforded significant changes in the measured binding affinity and target selectivity of the peptide. Computationally constructed homology models indicate that some modifications, such as incorporating two d‐cysteine residues, favourably alter the positions of key functional amino acid side chains, which is likely to cause changes in binding affinity, in agreement with measured surface plasmon resonance data.

A combined single-crystal X-ray diffraction and NMR crystallography study of a 1:1 cocrystal of two fungicides, namely di­thia­non and pyrimethanil, is presented. Specifically, the role of hydrogen bonding and C—H⋯π and S⋯O inter­molecular inter­actions is qu­anti­tatively investigated.

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A crystallographic study highlighting the benefits of a combined XRD and NMR approach in investigating both stability and variation within an organic multicomponent crystal.

Weak hydrogen bonds are increasingly hypothesized to play key roles in a wide range of chemistry from catalysis to gelation to polymer structure. Here, 15N/13C spin-echo magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) experiments are applied to “view” intermolecular CH···N hydrogen bonding in two selectively labeled organic compounds, 4-[15N] cyano-4′-[13C2] ethynylbiphenyl (1) and [15N3,13C6]-2,4,6-triethynyl-1,3,5-triazine (2). The synthesis of 2- 15 N 3 , 13 C 6 is reported here for the first time via a multistep procedure, where the key element is the reaction of [15N3]-2,4,6-trichloro-1,3,5-triazine (5) with [13C2]-[(trimethylsilyl)­ethynyl]zinc chloride (8) to afford its immediate precursor [15N3,13C6]-2,4,6-tris­[(trimethylsilyl)­ethynyl]-1,3,5-triazine (9). Experimentally determined hydrogen-bond-mediated 2h J CN couplings (4.7 ± 0.4 Hz (1) and 4.1 ± 0.3 Hz (2)) are compared with density functional theory (DFT) gauge-including projector augmented wave (GIPAW) calculations, whereby species-independent coupling values 2h K CN (29.0 × 1019 kg m–2 s–2 A–2 (1) and 27.9 × 1019 kg m–2 s–2 A–2 (2)) quantitatively demonstrate the J couplings for these “weak” CH···N hydrogen bonds to be of a similar magnitude to those for conventionally observed NH···O hydrogen-bonding interactions in uracil (2h K NO: 28.1 and 36.8 × 1019 kg m–2 s–2 A–2). Moreover, the GIPAW calculations show a clear correlation between increasing 2h J CN (and 3h J CN) coupling and reducing C­(H)···N and H···N hydrogen-bonding distances, with the Fermi contact term accounting for at least 98% of the isotropic 2h J CN coupling.

Heteronuclear multiple‐quantum coherence (HMQC) pulse sequences for establishing heteronuclear correlation in solid‐state nuclear magnetic resonance (NMR) between 35Cl and 1H nuclei in chloride salts under fast (60 kHz) magic‐angle spinning (MAS) and at high magnetic field (a 1H Larmor frequency of 850 MHz) are investigated. Specifically, recoupling of the 35Cl–1H dipolar interaction using rotary resonance recoupling with phase inversion every rotor period or the symmetry‐based SR421 pulse sequences are compared. In our implementation of the population transfer (PT) dipolar (D) HMQC experiment, the satellite transitions of the 35Cl nuclei are saturated with an off‐resonance WURST sweep, at a low nutation frequency, over the second spinning sideband, whereby the WURST pulse must be of the same duration as the recoupling time. Numerical simulations of the 35Cl–1H MAS D‐HMQC experiment performed separately for each crystallite orientation in a powder provide insight into the orientation dependence of changes in the second‐order quadrupolar‐broadened 35Cl MAS NMR lineshape under the application of dipolar recoupling. Two‐dimensional 35Cl–1H PT‐D‐HMQC MAS NMR spectra are presented for the amino acids glycine·HCl and l‐tyrosine·HCl and the pharmaceuticals cimetidine·HCl, amitriptyline·HCl and lidocaine·HCl·H2O. Experimentally observed 35Cl lineshapes are compared with those simulated for 35Cl chemical shift and quadrupolar parameters as calculated using the gauge‐including projector‐augmented wave (GIPAW) method: the calculated quadrupolar product (PQ) values exceed those measured experimentally by a factor of between 1.3 and 1.9.

Single-crystal X-ray diffraction structures of the 5-amino-2-methylpyridinium hydrogen fumarate salt have been solved at 150 and 300 K (CCDC 1952142 and 1952143). A base-acid-base-acid ring is formed through pyridiniumcarboxylate and amine-carboxylate hydrogen bonds that hold together chains formed from hydrogen-bonded hydrogen fumarate ions. 1 H and 13 C chemical shifts as well as 14 N shifts that additionally depend on the quadrupolar interaction are determined by experimental magic angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) and gauge-including projector-augmented wave (GIPAW) calculation. Two-dimensional homonuclear 1 H-1 H double-quantum (DQ) MAS and heteronuclear 1 H-13 C and 14 N-1 H spectra are presented. Only small differences of up to 0.1 and 0.6 ppm for 1 H and 13 C are observed between GIPAW calculations starting with the two structures solved at 150 and 300 K (after geometry optimisation of atomic positions, but not unit cell parameters). A comparison of GIPAW-calculated 1 H chemical shifts for isolated molecules and the full crystal structures is indicative of hydrogen bonding strength.

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