Ligand-Induced Proton Transfer and Low-Barrier Hydrogen Bond Revealed by X-ray Crystallography.

Ligand binding can change the pKa of protein residues and influence enzyme catalysis. Herein, we report three ultrahigh resolution X-ray crystal structures of CTX-M β-lactamase, directly visualizing protonation state changes along the enzymatic pathway: apo protein at 0.79 Å, precovalent complex with nonelectrophilic ligand at 0.

Identification and Characterization of Noncovalent Interactions That Drive Binding and Specificity in DD-Peptidases and β-Lactamases.

Bacterial resistance to standard (i.e., β-lactam-based) antibiotics has become a global pandemic.

Can molecular dynamics and QM/MM solve the penicillin binding protein protonation puzzle?

Benzylpenicillin, a member of the β-lactam antibiotic class, has been widely used to combat bacterial infections since 1947. The general mechanism is well-known: a serine protease enzyme (i.e.

How does catalase release nitric oxide? A computational structure-activity relationship study.

Hydroxyurea (HU) is the only FDA approved medication for treating sickle cell disease in adults. The primary mechanism of action is pharmacological elevation of nitric oxide (NO) levels which induces propagation of fetal hemoglobin. HU is known to undergo redox reactions with heme based enzymes like hemoglobin and catalase to produce NO.

Unlocking the binding and reaction mechanism of hydroxyurea substrates as biological nitric oxide donors.

Hydroxyurea is the only FDA approved treatment of sickle cell disease. It is believed that the primary mechanism of action is associated with the pharmacological elevation of nitric oxide in the blood; however, the exact details of this are still unclear. In the current work, we investigate the atomic level details of this process using a combination of flexible-ligand/flexible-receptor virtual screening coupled with energetic analysis that decomposes interaction energies.

Characterizing the mechanism of the double proton transfer in the formamide dimer.

The double proton transfer in the formamide dimer is characterized computationally by combining density functional theory and ab initio methods. The intrinsic reaction coordinate (IRC) is obtained at the B3LYP level of theory. Energies of several points along the IRC are treated by the more rigorous focal point method to test the validity of the B3LYP functional.

Noncovalent interactions of a benzo[a]pyrene diol epoxide with DNA base pairs: insight into the formation of adducts of (+)-BaP DE-2 with DNA.

Noncovalent complexes of a tumorigenic benzo[a]pyrene diol epoxide with the guanine-cytosine (GC) and adenine-thymine (AT) base pairs have been examined computationally. (+)-BaP DE-2 forms covalent adducts with DNA via nucleophilic attack on the (+)-BaP DE-2 epoxide. Computational results predict five thermodynamically accessible complexes of AT with (+)-BaP DE-2 that are compatible with intact DNA.

Short intramolecular hydrogen bonds: derivatives of malonaldehyde with symmetrical substituents.

A systematic study of various derivatives of malonaldehyde has been carried out to explore very short hydrogen bonds (r(OO) < 2.450 A). Various electron-withdrawing groups, including CN, NO(2), and BH(2), have been attached to the central carbon atom, C(2).