34 research outputs found
Experience of physical violence and mental health among young men and women: a population-based study in Sweden
Photoexcitation and ionization in carbon dioxide: Theoretical studies in the separated-channel static-exchange approximation
Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein Bound Ligands
A previously studied congeneric series
of thermolysin inhibitors
addressing the solvent-accessible S<sub>2</sub>′ pocket with
different hydrophobic substituents showed modulations of the surface
water layers coating the protein-bound inhibitors. Increasing stabilization
of water molecules resulted in an enthalpically more favorable binding
signature, overall enhancing affinity. Based on this observation,
we optimized the series by designing tailored P<sub>2</sub>′
substituents to improve and further stabilize the surface water network.
MD simulations were applied to predict the putative water pattern
around the bound ligands. Subsequently, the inhibitors were synthesized
and characterized by high-resolution crystallography, microcalorimetry,
and surface plasmon resonance. One of the designed inhibitors established
the most pronounced water network of all inhibitors tested so far,
composed of several fused water polygons, and showed 50-fold affinity
enhancement with respect to the original methylated parent ligand.
Notably, the inhibitor forming the most perfect water network also
showed significantly prolonged residence time compared to the other
tested inhibitors
Impact of Preoperative Symptoms and Revascularized Arterial Segment in Patients With Chronic Limb-Threatening Ischemia
Price for Opening the Transient Specificity Pocket in Human Aldose Reductase upon Ligand Binding Structural, Thermodynamic, Kinetic, and Computational Analysis
Insights into the thermodynamic and
kinetic signature of the transient
opening of a protein-binding pocket resulting from accommodation of
suitable substituents attached to a given parent ligand scaffold are
presented. As a target, we selected human aldose reductase, an enzyme
involved in the development of late-stage diabetic complications.
To recognize a large scope of substrate molecules, this reductase
opens a transient specificity pocket. The pocket-opening step was
studied by X-ray crystallography, microcalorimetry, and surface plasmon
resonance using a narrow series of 2-carbamoyl-phenoxy-acetic acid
derivatives. Molecular dynamics simulations suggest that pocket opening
occurs only once an appropriate substituent is attached to the parent
scaffold. Transient pocket opening of the uncomplexed protein is hardly
recorded. Hydration-site analysis suggests that up to five water molecules
entering the opened pocket cannot stabilize this state. Sole substitution
with a benzyl group stabilizes the opened state, and the energetic
barrier for opening is estimated to be ∼5 kJ/mol. Additional
decoration of the pocket-opening benzyl substituent with a nitro group
results in a huge enthalpy-driven potency increase; on the other hand,
an isosteric carboxylic acid group reduces the potency 1000-fold,
and binding occurs without pocket opening. We suggest a ligand induced-fit
mechanism for the pocket-opening step, which, however, does not represent
the rate-determining step in binding kinetics