Structural Polymorphism of Guanine Quadruplex-Containing Regions in Human Promoters.

Intramolecular guanine quadruplexes (G4s) are non-canonical nucleic acid structures formed by four guanine (G)-rich tracts that assemble into a core of stacked planar tetrads. G4-forming DNA sequences are enriched in gene promoters and are implicated in the control of gene expression. Most G4-forming DNA contains more G residues than can simultaneously be incorporated into the core resulting in a variety of different possible G4 structures. Although this kind of structural polymorphism is well recognized in the literature, there remain unanswered questions regarding possible connections between G4 polymorphism and biological function. Here we report a detailed bioinformatic survey of G4 polymorphism in human gene promoter regions. Our analysis is based on identifying G4-containing regions (G4CRs), which we define as stretches of DNA in which every residue can form part of a G4. We found that G4CRs with higher degrees of polymorphism are more tightly clustered near transcription sites and tend to contain G4s with shorter loops and bulges. Furthermore, we found that G4CRs with well-characterized biological functions tended to be longer and more polymorphic than genome-wide averages. These results represent new evidence linking G4 polymorphism to biological function and provide new criteria for identifying biologically relevant G4-forming regions from genomic data.

Understanding Terminal versus Bridging End-on N2 Coordination in Transition Metal Complexes.

Terminal and bridging end-on coordination of N2 to transition metal complexes offer possibilities for distinct pathways in ammonia synthesis and N2 functionalization. Here we elucidate the fundamental factors controlling the two binding modes and determining which is favored for a given metal-ligand system, using both quantitative density functional theory (DFT) and qualitative molecular orbital (MO) analyses. The Gibbs free energy for converting two terminal MN2 complexes into a bridging MNNM complex and a free N2 molecule (2ΔGeq°) is examined through systematic variations of the metal and ligands; values of ΔGeq° range between +9.1 and -24.0 kcal/mol per M-N2 bond. We propose a model that accounts for these broad variations by assigning a fixed π-bond order (BOπ) to the triatomic terminal MNN moiety that is equal to that of the free N2 molecule, and a variable BOπ to the bridging complexes based on the character (bonding or antibonding) and occupancy of the π-MOs in the tetratomic MNNM core. When the conversion from terminal to bridging coordination and free N2 is associated with an increase in the number of π-bonds (ΔBOeqπ > 0), the bridging mode is greatly favored; this condition is satisfied when each metal provides 1, 2, or 3 electrons to the π-MOs of the MNNM core. When each metal in the bridging complex provides 4 electrons to the MNNM π-MOs, ΔBOeqπ = 0; the equilibrium in this case is approximately ergoneutral and the direction can be shifted by dispersion interactions.