The founding in 1965 of what is now called the Cambridge Structural Database (CSD) has reaped dividends in numerous and diverse areas of chemical research. Each of the million or so crystal structures in the database was solved for its own particular reason, but collected together, the structures can be reused to address a multitude of new problems. In this Review, which is focused mainly on the last 10 years, we chronicle the contribution of the CSD to research into molecular geometries, molecular interactions, and molecular assemblies and demonstrate its value in the design of biologically active molecules and the solid forms in which they are delivered. Its potential in other commercially relevant areas is described, including gas storage and delivery, thin films, and (opto)electronics. The CSD also aids the solution of new crystal structures. Because no scientific instrument is without shortcomings, the limitations of CSD research are assessed. We emphasize the importance of maintaining database quality: notwithstanding the arrival of big data and machine learning, it remains perilous to ignore the principle of garbage in, garbage out. Finally, we explain why the CSD must evolve with the world around it to ensure it remains fit for purpose in the years ahead.

A Million Crystal Structures: The Whole Is Greater than the Sum of Its Parts

Carbon bonds (C-bonds) are the highly directional noncovalent interactions between carbonyl-oxygen acceptors and sp3 -hybridized-carbon σ-hole donors through n→σ* electron delocalization. We have shown the ubiquitous existence of C-bonds in proteins with the help of careful protein structure analysis and quantum calculations, and have precisely determined C-bond energies. The importance of conventional noncovalent interactions such as hydrogen bond (H-bonds) and halogen bond (X-bonds) in the structure and function of biological molecules are well established, while carbon bonds C-bonds have still to be recognized. We have shown that C-bonds are present in proteins, contribute enthalpically to the overall hydrophobic interaction and play a significant role in the photodissociation mechanism of myoglobin and the binding of nucleobases to proteins.

Noncovalent Carbon-Bonding Interactions in Proteins

Carbonyl-carbonyl (CO···CO) interactions are emerging noncovalent interactions found in many small molecules, polyesters, peptides and proteins. However, little is known about the effect of the relative orientation of the two carbonyl groups on the nature of these interactions. Herein, we first show that simple homodimers of acetone and formaldehyde can serve as models to understand the effect of relative orientations of the two carbonyl groups on the nature of CO···CO interactions. Further, from a comprehensive statistical analysis of molecules having inter- or intramolecular CO···CO interactions, we show that the molecules can be broadly categorized into six different structural motifs (I-VI). The analysis of pyramidality of the acceptor carbon atoms in these motifs and natural bond orbital (NBO) analysis suggest that the relative orientation of the two interacting carbonyl groups determines whether the orbital interaction between the two carbonyl groups would be n → π* or π → π* or a combination of both.

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Relative orientation of the carbonyl groups determines the nature of orbital interactions in carbonyl–carbonyl short contacts

Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50 = 11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 A resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels. Here authors reveal the cryo-EM structure of LqhIII bound to NaV1.5 which shows that LqhIII traps the gating charges of the S4 segment in a unique intermediate-activated state and explains why LqhIII slows inactivation of NaV channels but does not open them.

/pdf/structural-basis-for-voltage-sensor-trapping-of-the-cardiac-4tgrqof7i7.pdf

Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin

We performed a comprehensive analysis of intermolecular carbonyl-carbonyl interactions in transition-metal complexes. Those interactions can be classified in two main types depending on the organometallic or organic nature of the donor carbonyl: M-CO···CO and R-CO···CO, respectively. By means of a combined structural and computational study we unraveled their geometrical features and strength. Moreover, electronic structure, natural bond orbitals, energy decomposition analysis, and quantum theory of atoms in molecules calculations were performed to try to understand their nature. Remarkably, we discovered that these carbonyl-carbonyl contacts have several features of the n → π* interaction. The charge transfer from an oxygen lone pair to an empty antibonding π orbital of the acceptor carbonyl is also accompanied by an electrostatic Oδ-···Cδ+ interaction. To the best of our knowledge this is the first report of an intermolecular n → π* interaction in metal complexes. These results might be significant, for instance, for the catalytic activation of carbonyl-containing small molecules with metal compounds or in the design of hybrid organic-inorganic materials, metal-organic frameworks, and other extended structures.

Intermolecular Carbonyl···Carbonyl Interactions in Transition-Metal Complexes.

Carbonyl-carbonyl n→π* interactions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the π* orbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a "reciprocal" carbonyl-carbonyl interaction with substantial back and forth n→π* and π→π* electron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding.Carbonyl-carbonyl π* non covalent interactions affect the structure and stability of small molecules and proteins. Here, the authors carry out experimental studies, analyses of crystallographic databases and theoretical calculations to describe an additional type of carbonyl-carbonyl interaction.

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Reciprocal carbonyl-carbonyl interactions in small molecules and proteins

N,N′-Di(acylamino)-2,5-diketopiperazines: Strategic Incorporation of Reciprocal n → π* Interactions in a Druglike Scaffold

Hypervalent aryliodoumiums are intensively investigated as arylating agents. They are excellent surrogates to aryl halides, and moreover they exhibit better reactivity, which allows the corresponding arylation reactions to be performed under mild conditions. In the past decades, acyclic aryliodoniums are widely explored as arylation agents. However, the unmet need for acyclic aryliodoniums is the improvement of their notoriously low reaction economy because the coproduced aryl iodides during the arylation are often wasted. Cyclic aryliodoniums have their intrinsic advantage in terms of reaction economy, and they have started to receive considerable attention due to their valuable synthetic applications to initiate cascade reactions, which can enable the construction of complex structures, including polycycles with potential pharmaceutical and functional properties. Here, we are summarizing the recent advances made in the research field of cyclic aryliodoniums, including the nascent design of aryliodonium species and their synthetic applications. First, the general preparation of typical diphenyl iodoniums is described, followed by the construction of heterocyclic iodoniums and monoaryl iodoniums. Then, the initiated arylations coupled with subsequent domino reactions are summarized to construct polycycles. Meanwhile, the advances in cyclic aryliodoniums for building biaryls including axial atropisomers are discussed in a systematic manner. Finally, a very recent advance of cyclic aryliodoniums employed as halogen-bonding organocatalysts is described.

https://pubs.acs.org/doi/pdf/10.1021/acs.chemrev.2c00591

Recent Progress in Cyclic Aryliodonium Chemistry: Syntheses and Applications

We report the solid-phase synthesis of N,N′-di(acylamino)-2,5-diketopiperazine, an acylhydrazide-based conformationally rigid 2,5-DKP scaffold having exocyclic N–N bonds. We also show that different combinations of acylhydrazides, carbazates, semicarbazides, amino acids, and primary amines can be used to synthesize a highly diverse collection of hybrid DKP molecules via the solid-phase submonomer synthesis route. Finally, we show incorporation of a methyl substituent in one of the carbon atoms of the DKP ring to generate chiral daa- and hybrid-DKPs without compromising the synthetic efficiency.

Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers

Here we report the design of N 2 -carboxy-4-aryl-1,2,3-triazole-lysines (CATKs) and their site-specific incorporation into proteins via genetic code expansion. When introduced into the protein dimer interface, CATKs permitted spontaneous, proximity-driven, site-selective crosslinking to generate covalent protein dimers in living cells, with phenyl-bearing CATK- 1 exhibiting high reactivity toward the proximal Lys and Tyr. Furthermore, when introduced into the N -terminal β -strand of either a single-chain VHH antibody or a supercharged monobody, CATK- 1 enabled site-specific, inter-strand, orthogonal crosslinking with a proximal Tyr located on the opposing β -strand. Compared with a non-crosslinked monobody, the orthogonally crosslinked monobody displayed improved cellular uptake and enhanced proteolytic stability against an endosomal enzyme. The robust crosslinking reactivity of CATKs should facilitate the design of novel protein topologies with improved physicochemical properties.

https://rss.onlinelibrary.wiley.com/doi/am-pdf/10.1002/anie.202202657

Abdur Rahim

Papers

Reciprocal carbonyl-carbonyl interactions in small molecules and proteins

N,N′-Di(acylamino)-2,5-diketopiperazines: Strategic Incorporation of Reciprocal n → π* Interactions in a Druglike Scaffold

Recent Progress in Cyclic Aryliodonium Chemistry: Syntheses and Applications

Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers

Spontaneous Orthogonal Protein Crosslinking via a Genetically Encoded 2-Carboxy-4-Aryl-1,2,3-Triazole.