1,721,004 research outputs found
The conformational landscape of tartrate-based inhibitors of the TACE enzyme as revealed by Hamiltonian Replica Exchange simulation
No full textThe inhibitors of the Tumor Necrosis Factor-α Converting Enzyme represent promising tools for the treatment of Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. In this work, using Hamiltonian Replica Exchange Molecular Dynamics simulations and atomistic force field we perform an accurate structural characterization of a group of tartrate-based inhibitors. The simulations highlight a correlation between the conformational landscape in bulk solvent and inhibition potency. Since the structures in bulk solvent are much more compact than the crystallographic bound state, we formulate the hypothesis of a two-step docking mechanism: (i) formation of an intermediate between the compact, hydroxyl exposing conformations in solution and the catalytic zinc ion; (ii) structural rearrangement in the active site of TACE of the zinc-tethered drug in the final binding conformatio
A model of sympatric speciation through assortive mating
No full textA microscopic model is developed, within the frame of the theory of quantitative traits, to
study the combined effect of competition and assortativity on the sympatric speciation
process, i.e., speciation in the absence of geographical barriers. Two components of fitness are
considered: a static one that describes adaptation to environmental factors not related to the
population itself, and a dynamic one that accounts for interactions between organisms, e.g.
competition. A simulated annealing technique was applied in order to speed up simulations.
The simulations show that both in the case of flat and steep static fitness landscapes,
competition and assortativity do exert a synergistic effect on speciation. We also show that
competition acts as a stabilizing force against extinction due to random sampling in a finite
population. Finally, evidence is shown that speciation can be seen as a phase transition
Sympatric Speciation Through Assortative Mating in a Long-Range Cellular Automaton
No full textA probabilistic cellular automaton is developed to study the combined effect of competition and assortativity on the speciation process in the absence of geographical barriers. The model is studied in the case of long-range coupling. A simulated annealing technique was used in order to find the stationary distribution in reasonably short simulation times. Two components of fitness are considered: a static one that describes adaptation to environmental factors not related to the population itself, and a dynamic one that accounts for interactions between organisms such as competition. The simulations show that both in the case of flat and steep static fitness landscape, competition and assortativity do exert a synergistic effect on speciation. We also show that competition acts as a stabilizing force preventing the random sampling effects to drive one of the newborn populations to extinction. Finally, the variance of the frequency distribution is plotted as a function of competition and assortativity, obtaining a surface that shows a sharp transition from a very low (single species state) to a very high (multiple species state) level, therefore featuring as a phase transition diagram. Examination of the contour plots of the phase diagram graphycally highlights the synergetic effect
A toy model of polymer stretching
No full textWe present an extremely simplified model of multiple-domain polymer stretching in an atomic force microscopy experiment. We portray each module as a binary set of contacts and decompose the system energy into a harmonic term the cantilever and long-range interaction terms inside each domain. Exact equilibrium computations and Monte Carlo simulations qualitatively reproduce the experimental sawtooth pattern of force-extension profiles, corresponding in our model to first-order phase transitions. We study the influence of the coupling induced by the cantilever and the pulling speed on the relative heights of the force peaks. The results suggest that the increasing height of the critical force for subsequent unfolding events is an out-of-equilibrium effect due to a finite pulling speed. The dependence of the average unfolding force on the pulling speed is shown to reproduce the experimental logarithmic law
Integrated Approach Including Docking, MD Simulations, and Network Analysis Highlights the Action Mechanism of the Cardiac hERG Activator RPR260243
Full text linkhERG is a voltage-gatedpotassium channel involved inthe heartcontraction whose defections are associated with the cardiac arrhythmiaLong QT Syndrome type 2. The activator RPR260243 (RPR) representsa possible candidate to pharmacologically treat LQTS2 because it enhancesthe opening of the channel. However, the molecular detail of its actionmechanism remains quite elusive. Here, we address the problem usinga combination of docking, molecular dynamics simulations, and networkanalysis. We show that the drug preferably binds at the interfacebetween the voltage sensor and the pore, enhancing the canonical activationpath and determining a whole-structure rearrangement of the channelthat slightly impairs inactivation
Testing Simplified Proteins Models of the hPin1 WW Domain
Full text linkAbstractThe WW domain of the human Pin1 protein for its simple topology and large amount of experimental data is an ideal candidate to assess theoretical approaches to protein folding. The purpose of this work is to compare the reliability of the chemically based Sorenson/Head-Gordon (SHG) model and a standard native centric model in reproducing, through molecular dynamics simulations, some of the well known features of the folding transition of this small domain. Our results show that the Gō model correctly reproduces the cooperative, two-state, folding mechanism of the WW-domain, while the SHG model predicts a transition occurring in two stages: a collapse, followed by a structural rearrangement. The lack of a cooperative folding in the SHG simulations appears to be related to the nonfunnel shape of the energy landscape featuring a partitioning of the native valley in subbasins corresponding to different chain chiralities. However, the SHG approach remains more reliable in estimating the Φ-values with respect to Gō-like description. This may suggest that the WW-domain folding process is stirred by energetic and topological factors as well, and it highlights the better suitability of chemically based models in simulating mutations
Membrane composition allows the optimization of berberine encapsulation in liposomes
No full textBerberine (BBR) is a natural molecule with noteworthy pharmacological properties, including the prevention
of antibiotic resistance in Gram-negative bacteria. However, its oral bioavailability is poor, thus resulting in an impaired absorption and efficacy in humans. In combination with other drugs, liposomes have been shown to enhance the availability of the drug, representing a smart delivery system to target tissues and reduce negative side effects. To date, there is a lack of studies on BBR and liposomes that enable the rationalization and molecular-based design of such formulations for future use in humans. In this work, the encapsulation of BBR into liposomes is proposed to overcome current limitations using a combination of experimental and computational assays to rationalize the membrane composition of liposomes that maximizes BBR encapsulation. First, the encapsulation efficiency was measured for several membrane compositions, revealing that it is enhanced by cholesteryl hemisuccinate and, to a lesser extent, by cholesterol. The physical basis of the BBR encapsulation efficiency and permeability was clarified using molecular dynamics simulation: using the lipid composition, one can tune the capability of membranes to attract, i.e., to adsorb, the molecules onto their surface. Overall, these findings suggest a rational strategy to maximize the encapsulation efficiency of liposomes by using negatively charged lipids, thus representing the basis for designing delivery systems for BBR, useful to treat, e.g., antibiotic resistance
A computational study of ion current modulation in hVDAC3 induced by disulfide bonds
No full textThe human VDAC channel exists in three isoforms characterized by high sequence homology and structural sim- ilarity. Yet the function and mode of action of hVDAC3 are still elusive. The presence of six surface cysteines ex- posed to the oxidizing environment of the mitochondrial inter-membrane space suggests the possible establishment of intramolecular disulfide bonds. Two natural candidates for disulfide bridge formation are Cys2 and Cys8 that, located on the flexible N-terminal domain, can easily come in contact. A third potentially im- portant residue is Cys122 that is close to Cys2 in the homology model of VDAC3. Here we analyzed the impact of SS bonds through molecular dynamics simulations of derivatives of hVDAC3 (dubbed SS-2-8, SS-2-122, SS-8- 122) including a single disulfide bond. Simulations showed that in SS-8-122, the fragment 1-7 crosses the top part of the barrel partially occluding the pore and causing a 20% drop of conductance. In order to identify other potential channel-occluding disulfide bonds, we used a set of neural networks and structural bioinformatics al- gorithms, after filtering with the steric constraints imposed by the 3D-structure. We identified other three spe- cies, namely SS-8-65, SS-2-36 and SS-8-36. While the conductance of SS-8-65 and SS-2-36 is about 30% lower than that of the species without disulfide bonds, the conductance of SS-8-36 was 40–50% lower. The results show how VDAC3 is able to modulate its pore size and current by exploiting the mobility of the N-terminal and forming, upon external stimuli, disulfide bridges with cysteine residues located on the barrel and exposed to the inter-membrane space
Chemical–physical analysis of a tartrate model compound for TACE inhibition
No full textWe have synthesized and done an extensive chemical–physical analysis of the behavior of a new compound,
named MBET306, a synthetic precursor of the recently discovered tartrate-based inhibitors of the protein
Tumor Necrosis factor-a Converting Enzyme (TACE). Experimental and theoretical data have shown that in
water solution MBET306 is overwhelmingly found as a monoanion at physiological pH, in a conformation
that differs substantially from that detected in the known co-crystal structures of MBET306 derivatives bound
to TACE. The body of collected experimental and theoretical data indicates that the monoanionic species
binds Zn(II) inducing a strong stabilization of the crystal-like arrangement of the central tartrate zinc-binding
group, lending support for a two step TACE docking mechanism via a zinc-bound intermediate. The
thorough chemical–physical characterization of the conformational behavior of free and zinc-bound
MBET306 in water bulk solution opens new avenues for the rational drug design of tartrate-based highly
specific TACE inhibitor
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