Facile C_sp²-C_sp² bond cleavage in oxalic acid-derived radicals

Oxalate decarboxylase (OxDC) catalyzes the Mn-dependent conversion of the oxalate monoanion into CO2 and formate. Many questions remain about the catalytic mechanism of OxDC although it has been proposed that the reaction proceeds via substrate-based radical intermediates. Using coupled cluster theory combined with implicit solvation models we have examined the effects of radical formation on the structure and reactivity of oxalic acid-derived radicals in aqueous solution. Our results show that the calculated solution-phase free-energy barrier for C–C bond cleavage to form CO2 is decreased from 34.2 kcal/mol for oxalic acid to only 9.3 kcal/mol and a maximum of 3.5 kcal/mol for the cationic and neutral oxalic acid-derived radicals, respectively. These studies also show that the C–C σ bonding orbital of the radical cation contains only a single electron, giving rise to an elongated C–C bond distance of 1.7 Å; a similar lengthening of the C–C bond is not observed for the neutral radical. This study provides new chemical insights into the structure and stability of plausible intermediates in the catalytic mechanism of OxDC, and suggests that removal of an electron to form a radical (with or without the concomitant loss of a proton) may be a general strategy for cleaving the unreactive C–C bonds between adjacent sp2-hybridized carbon atoms

Structure and Biophysics for a Six Letter DNA Alphabet that Includes Imidazo[1,2-a]-1,3,5-triazine-2(8H)-4(3H)-dione (X) and 2,4-Diaminopyrimidine (K)

A goal of synthetic biology is to develop new nucleobases that retain the desirable properties of natural nucleobases at the same time as expanding the genetic alphabet. The nonstandard Watson-Crick pair between imidazo[1,2-a]-1,3,5-triazine-2(8H)-4(3H)-dione (X) and 2,4-diaminopyrimidine (K) does exactly this, pairing via complementary arrangements of hydrogen bonding in these two nucleobases, which do not complement any natural nucleobase. Here, we report the crystal structure of a duplex DNA oligonucleotide in B-form including two consecutive X:K pairs in GATCXK DNA determined as a host-guest complex at 1.75 Å resolution. X:K pairs have significant propeller twist angles, similar to those observed for A:T pairs, and a calculated hydrogen bonding pairing energy that is weaker than that of A:T. Thus, although inclusion of X:K pairs results in a duplex DNA structure that is globally similar to that of an analogous G:C structure, the X:K pairs locally and energetically more closely resemble A:T pairs

Octahedral Trifluoromagnesate, an Anomalous Metal Fluoride Species, Stabilizes the Transition State in a Biological Motor

Isoelectronic metal fluoride transition state analogue (TSA) complexes, MgF3- and AlF4-, have proven to be immensely useful in understanding mechanisms of biological motors utilizing phosphoryl transfer. Here we report a previously unobserved octahedral TSA complex, MgF3(H2O)-, in a 1.5 Å resolution Zika virus NS3 helicase crystal structure. 19F NMR provided independent validation and also the direct observation of conformational tightening resulting from ssRNA binding in solution. The TSA stabilizes the two conformations of motif V of the helicase that link ATP hydrolysis with mechanical work. DFT analysis further validated the MgF3(H2O)- species, indicating the significance of this TSA for studies of biological motors

Metal Fluorides:Tools for Structural and Computational Analysis of Phosphoryl Transfer Enzymes

The phosphoryl group, PO3-, is the dynamic structural unit in the biological chemistry of phosphorus. Its transfer from a donor to an acceptor atom, with oxygen much more prevalent than nitrogen, carbon, or sulfur, is at the core of a great majority of enzyme-catalyzed reactions involving phosphate esters, anhydrides, amidates, and phosphorothioates. The serendipitous discovery that the phosphoryl group could be labeled by "nuclear mutation," by substitution of PO3- by MgF3- or AlF4-, has underpinned the application of metal fluoride (MF x ) complexes to mimic transition states for enzymatic phosphoryl transfer reactions, with sufficient stability for experimental analysis. Protein crystallography in the solid state and 19F NMR in solution have enabled direct observation of ternary and quaternary protein complexes embracing MF x transition state models with precision. These studies have underpinned a radically new mechanistic approach to enzyme catalysis for a huge range of phosphoryl transfer processes, as varied as kinases, phosphatases, phosphomutases, and phosphohydrolases. The results, without exception, have endorsed trigonal bipyramidal geometry (tbp) for concerted, "in-line" stereochemistry of phosphoryl transfer. QM computations have established the validity of tbp MF x complexes as reliable models for true transition states, delivering similar bond lengths, coordination to essential metal ions, and virtually identical hydrogen bond networks. The emergence of protein control of reactant orbital overlap between bond-forming species within enzyme transition states is a new challenging theme for wider exploration

A GAP‐GTPase‐GDP‐P i Intermediate Crystal Structure Analyzed by DFT Shows GTP Hydrolysis Involves Serial Proton Transfers

Cell signaling by small G proteins uses an ON to OFF signal based on conformational changes following the hydrolysis of GTP to GDP and release of dihydrogen phosphate (Pi). The catalytic mechanism of GTP hydrolysis by RhoA is strongly accelerated by a GAP protein and is now well defined, but timing of inorganic phosphate release and signal change remains unresolved. We have generated a quaternary complex for RhoA‐GAP‐GDP‐Pi. Its 1.75 Å crystal structure shows geometry for ionic and hydrogen bond coordination of GDP and Pi in an intermediate state. It enables the selection of a QM core for DFT exploration of a 20 H‐bonded network. This identifies serial locations of the two mobile protons from the original nucleophilic water molecule, showing how they move in three rational steps to form a stable quaternary complex. It also suggests how two additional proton transfer steps can facilitate Pi release

The Great Diversity of HMX Conformers: Probing the Potential Energy Surface Using CCSD(T)

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of <i>what</i> all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD­(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX

The Great Diversity of HMX Conformers: Probing the Potential Energy Surface Using CCSD(T)

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of <i>what</i> all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD­(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX

The Great Diversity of HMX Conformers: Probing the Potential Energy Surface Using CCSD(T)

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of <i>what</i> all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD­(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX

The Great Diversity of HMX Conformers: Probing the Potential Energy Surface Using CCSD(T)

The octahydro-1,3,5,7-tetranitro-1,3,5,7-tetraazocine (HMX) molecule is a very commonly studied system, in all 3 phases, because of its importance as an explosive; however, no one has ever attempted a systematic study of <i>what</i> all the major gas-phase conformers are. This is critical to a mechanistic study of the kinetics involved, as well as the viability of various crystalline polymorphs based on the gas-phase conformers. We have used existing knowledge of basic cyclooctane chemistry to survey all possible HMX conformers based on its fundamental ring structure. After studying what geometries are possible after second-order many-body perturbation theory (MBPT(2)) geometry optimization, we calculated the energetics using coupled cluster singles, doubles, and perturbative triples (CCSD­(T))/cc-pVTZ. These highly accurate energies allow us to better calculate starting points for future mechanistic studies. Additionally, the plethora of structures are compared to existing experimental data of crystals. It is found that the crystal field effect is sometimes large and sometimes small for HMX