Insights into the Complex Formed by Matrix Metalloproteinase-2 and Alloxan Inhibitors: Molecular Dynamics Simulations and Free Energy Calculations

Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S1′ specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S1′ subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC50 = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases

Lattice Boltzmann study of evaporation phenomena

Evaporation phenomena are having a resurgent interest in the recent years thanks to new techniques that allow for better flow visualization and microfabrication techniques of surfaces with interesting wetting properties. From the theoretical point of view the development of simulation techniques for evaporation phenomena is a challenging work due to the presence of moving interfaces and multiphase flows. Thanks to its mesoscopic nature, the Lattice Boltzmann method is an ideal candidate for the simulation of evaporation phenomena. Here we present a Lattice Boltzmann algorithm capable to correctly reproduce the diffusion-limited evaporation dynamics. We apply this numerical method to study the dynamics of multiple droplets evaporating together and we compare the results with experimental measures. We show that the presence of other droplets can dramatically increase the evaporation lifetime compared to the single droplet case; we also investigate the competition between convection and collective effects. We then develop a theory to predict the instability behaviour of liquid fronts in two dimensional confined geometries and we consider the interplay between capillary forces, wettability gradients and phase changes. We use LB simulations to investigate the effect of a three dimensional geometry that cannot be taken into account in the analytical theory. Finally we investigate the effect of flows on droplet evaporation. We consider both buoyancy induced and external flows. We show that even when diffusion is the dominant mechanism, flow effects are not negligible.</p

Lattice Boltzmann study of evaporation phenomena

Evaporation phenomena are having a resurgent interest in the recent years thanks to new techniques that allow for better flow visualization and microfabrication techniques of surfaces with interesting wetting properties. From the theoretical point of view the development of simulation techniques for evaporation phenomena is a challenging work due to the presence of moving interfaces and multiphase flows. Thanks to its mesoscopic nature, the Lattice Boltzmann method is an ideal candidate for the simulation of evaporation phenomena. Here we present a Lattice Boltzmann algorithm capable to correctly reproduce the diffusion-limited evaporation dynamics. We apply this numerical method to study the dynamics of multiple droplets evaporating together and we compare the results with experimental measures. We show that the presence of other droplets can dramatically increase the evaporation lifetime compared to the single droplet case; we also investigate the competition between convection and collective effects. We then develop a theory to predict the instability behaviour of liquid fronts in two dimensional confined geometries and we consider the interplay between capillary forces, wettability gradients and phase changes. We use LB simulations to investigate the effect of a three dimensional geometry that cannot be taken into account in the analytical theory. Finally we investigate the effect of flows on droplet evaporation. We consider both buoyancy induced and external flows. We show that even when diffusion is the dominant mechanism, flow effects are not negligible

Using evaporation to control capillary instabilities in micro-systems

The instabilities of fluid interfaces represent both a limitation and an opportunity for the fabrication of small-scale devices. Just as non-uniform capillary pressures can destroy micro-electrical mechanical systems (MEMS), so they can guide the assembly of novel solid and fluid structures. In many such applications the interface appears during an evaporation process and is therefore only present temporarily. It is commonly assumed that this evaporation simply guides the interface through a sequence of equilibrium configurations, and that the rate of evaporation only sets the timescale of this sequence. Here, we use Lattice-Boltzmann simulations and a theoretical analysis to show that, in fact, the rate of evaporation can be a factor in determining the onset and form of dynamical capillary instabilities. Our results shed light on the role of evaporation in previous experiments, and open the possibility of exploiting diffusive mass transfer to directly control capillary flows in MEMS applications

Kidney CLC-K Chloride Channels Show Differential Pharmacological Profiles Depending on the Heterologous Expression System

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Thermodynamic cycle. Events A and B represent the binding of two different ligands to a protein, events C and D indicate the conversion from one ligand to the other in the bound and hydrated states, respectively.

<p>The free energy differences between the processes A and C can be obtained calculating the free energy differences between B and D.</p