Halogen Interactions in Protein–Ligand Complexes: Implications of Halogen Bonding for Rational Drug Design

Halogen bonding interactions between halogenated ligands and proteins were examined using the crystal structures deposited to date in the PDB. The data was analyzed as a function of halogen bonding to main chain Lewis bases, viz. oxygen of backbone carbonyl and backbone amide nitrogen. This analysis also examined halogen bonding to side-chain Lewis bases (O, N, and S) and to the electron-rich aromatic amino acids. All interactions were restricted to van der Waals radii with respective atoms. The data reveals that while fluorine and chlorine have strong tendencies favoring interactions with the backbone Lewis bases at glycine, the trend is not restricted to the achiral amino acid backbone for larger halogens. Halogen side-chain interactions are not restricted to amino acids containing O, N, and S as Lewis bases. Electron-rich aromatic amino acids host a high frequency of halogen bonds as does Leu. A closer examination of the latter hydrophobic side chain reveals that the “propensity of interactions” of halogen ligands at this oily residue is an outcome of strong classical halogen bonds with Lewis bases in the vicinity. Finally, an examination of Θ₁ (C–X···O and C–X···N) and Θ₂ (X···O–Z and X···N–Z) angles reveals that very few ligands adopt classical halogen bonding angles, suggesting that steric and other factors may influence these angles. The data is discussed in the context of ligand design for pharmaceutical applications

A Metal Organic Framework with Spherical Protein Nodes: Rational Chemical Design of 3D Protein Crystals

We describe here the construction of a three-dimensional, porous, crystalline framework formed by spherical protein nodes that assemble into a prescribed lattice arrangement through metal–organic linker-directed interactions. The octahedral iron storage enzyme, ferritin, was engineered in its <i>C</i>₃ symmetric pores with tripodal Zn coordination sites. Dynamic light scattering and crystallographic studies established that this Zn-ferritin construct could robustly self-assemble into the desired bcc-type crystals upon coordination of a ditopic linker bearing hydroxamic acid functional groups. This system represents the first example of a ternary protein–metal–organic crystalline framework whose formation is fully dependent on each of its three components

A Metal Organic Framework with Spherical Protein Nodes: Rational Chemical Design of 3D Protein Crystals

We describe here the construction of a three-dimensional, porous, crystalline framework formed by spherical protein nodes that assemble into a prescribed lattice arrangement through metal–organic linker-directed interactions. The octahedral iron storage enzyme, ferritin, was engineered in its <i>C</i>₃ symmetric pores with tripodal Zn coordination sites. Dynamic light scattering and crystallographic studies established that this Zn-ferritin construct could robustly self-assemble into the desired bcc-type crystals upon coordination of a ditopic linker bearing hydroxamic acid functional groups. This system represents the first example of a ternary protein–metal–organic crystalline framework whose formation is fully dependent on each of its three components

A Metal Organic Framework with Spherical Protein Nodes: Rational Chemical Design of 3D Protein Crystals

We describe here the construction of a three-dimensional, porous, crystalline framework formed by spherical protein nodes that assemble into a prescribed lattice arrangement through metal–organic linker-directed interactions. The octahedral iron storage enzyme, ferritin, was engineered in its <i>C</i>₃ symmetric pores with tripodal Zn coordination sites. Dynamic light scattering and crystallographic studies established that this Zn-ferritin construct could robustly self-assemble into the desired bcc-type crystals upon coordination of a ditopic linker bearing hydroxamic acid functional groups. This system represents the first example of a ternary protein–metal–organic crystalline framework whose formation is fully dependent on each of its three components

Synthetic Modularity of Protein–Metal–Organic Frameworks

Previously, we adopted the construction principles of metal–organic frameworks (MOFs) to design a 3D crystalline protein lattice in which pseudospherical ferritin nodes decorated on their <i>C</i>₃ symmetric vertices with Zn coordination sites were connected via a ditopic benzene-dihydroxamate linker. In this work, we have systematically varied both the metal ions presented at the vertices of the ferritin nodes (Zn­(II), Ni­(II), and Co­(II)) and the synthetic dihydroxamate linkers, which yielded an expanded library of 15 ferritin–MOFs with the expected body-centered (cubic or tetragonal) lattice arrangements. Crystallographic and small-angle X-ray scattering (SAXS) analyses indicate that lattice symmetries and dimensions of ferritin–MOFs can be dictated by both the metal and linker components. SAXS measurements on bulk crystalline samples reveal that some ferritin–MOFs can adopt multiple lattice conformations, suggesting dynamic behavior. This work establishes that the self-assembly of ferritin–MOFs is highly robust and that the synthetic modularity that underlies the structural diversity of conventional MOFs can also be applied to the self-assembly of protein-based crystalline materials