0000000000418782
AUTHOR
Lalita Uribe
A fundamental catalytic difference between zinc and manganese dependent enzymes revealed in a bacterial isatin hydrolase
Scientific reports 8(1), 13104 (2018). doi:10.1038/s41598-018-31259-y
Structural Origin of Metal Specificity in Isatin Hydrolase from Labrenzia aggregata Investigated by Computer Simulations.
We performed quantum-chemical calculations, ab initio molecular dynamics, hybrid quantum mechanics/molecular mechanics (QM/MM) and enhanced sampling metadynamics simulations to investigate the origin of metal specificity in isatin hydrolase from Labrenzia aggregata. The peculiar octahedral binding geometry of the Mn2+ ion in the Michaelis complex includes both the isatin substrate and the catalytic water within the first coordination shell of the cation. Our calculations show that the same arrangement of the ligands cannot be efficiently achieved in the presence of other small divalent metal cations such as Zn2+ or Cu2+ . On the contrary, bulkier alkaline-earth cations such as Mg2+ , which …
Comparative Study of the Mechanical Unfolding Pathways of α- and β-Peptides
Using molecular simulations, we analyze the unfolding pathways of various peptides. We compare the mechanical unfolding of a β-alanine's octamer (β-HAla8) and an α-alanine's decamer (α-Ala10). Using force-probe molecular-dynamics simulations, to induce unfolding, we show that the 3(14)-helix formed by β-HAla8 is mechanically more stable than the α-helix formed by α-Ala10, although both structures are stabilized by six hydrogen bonds. Additionally, computations of the potential of mean force validate this result and show that also the thermal stability of the 3(14)-helix is higher. It is demonstrated that β-HAla8 unfolds in a two-step fashion with a stable intermediate. This is contrasted wi…
Determining Factors for the Unfolding Pathway of Peptides, Peptoids, and Peptidic Foldamers.
We present a study of the mechanical unfolding pathway of five different oligomers (α-peptide, β-peptide, δ-aromatic-peptides, α/γ-peptides, and β-peptoids), adopting stable helix conformations. Using force-probe molecular dynamics, we identify the determining structural factors for the unfolding pathways and reveal the interplay between the hydrogen bond strength and the backbone rigidity in the stabilization of their helix conformations. On the basis of their behavior, we classify the oligomers in four groups and deduce a set of rules for the prediction of the unfolding pathways of small foldamers.
Mechanical unfolding pathway of a model β-peptide foldamer.
Foldamers constructed from oligomers of β-peptides form stable secondary helix structures already for small chain lengths, which makes them ideal candidates for the investigation of the (un)folding of polypeptides. Here, the results of molecular simulations of the mechanical unfolding of a β-heptapeptide in methanol solvent revealing the detailed unfolding pathway are reported. The unfolding process is shown to proceed via a stable intermediate even for such a small system. This result is arrived at performing non-equilibrium force ramp simulations employing different pulling velocities and also using standard calculations of the potential of mean force, i.e., the free energy as a function …