EQeq+C: An Empirical Bond-Order-Corrected Extended Charge Equilibration Method.

The extended charge equilibration (EQeq) scheme computes atomic partial charges using the experimentally measured ionization potentials and electron affinities of atoms. However, EQeq erroneously predicts constant (environment independent) charges for high-oxidation-state transition metals in amine-templated metal oxide (ATMO) compounds, contrary to the variation observed in iterative Hirshfeld (Hirshfeld-I) charges, bond-valence sum calculations, and formal oxidation state calculations. To fix this problem, we present a simple, noniterative empirical pairwise correction based on the Pauling bond-order/distance relationship, which we denote EQeq+C. We parametrized the corrections to reproduce the Hirshfeld-I charges of ATMO compounds and REPEAT charges of metal organic framework (MOF) compounds. The EQeq+C correction fixes the metal charge problem and significantly improves the partial atomic charges compared to EQeq. We demonstrate the transferability of the parametrization by applying it to a set of unrelated dipeptides. After an initial parametrization, the EQeq+C correction requires minimal computational overhead, making it suitable for treating large unit cell solids and performing large-scale computational materials screening.

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

Treatment of latent tuberculosis infection remains an important goal of global TB eradication. To this end, targets that are essential for intracellular survival of Mycobacterium tuberculosis are particularly attractive. Arylamine N-acetyltransferase (NAT) represents such a target as it is, along with the enzymes encoded by the associated gene cluster, essential for mycobacterial survival inside macrophages and involved in cholesterol degradation. Cholesterol is likely to be the fuel for M. tuberculosis inside macrophages. Deleting the nat gene and inhibiting the NAT enzyme prevents survival of the microorganism in macrophages and induces cell wall alterations, rendering the mycobacterium sensitive to antibiotics to which it is normally resistant. To date, NAT from M. marinum (MMNAT) is considered the best available model for NAT from M. tuberculosis (TBNAT). The enzyme catalyses the acetylation and propionylation of arylamines and hydrazines. Hydralazine is a good acetyl and propionyl acceptor for both MMNAT and TBNAT. The MMNAT structure has been solved to 2.1 Å resolution following crystallisation in the presence of hydralazine and is compared to available NAT structures. From the mode of ligand binding, features of the binding pocket can be identified, which point to a novel mechanism for the acetylation reaction that results in a 3-methyltriazolo[3,4-a]phthalazine ring compound as product.