In silico investigation of Alsin RLD conformational dynamics and phosphoinositides binding mechanism

Alsin is a protein known for its major role in neuronal homeostasis and whose mutation is associated with early-onset neurodegenerative diseases. It has been shown that its relocalization from the cytoplasm to the cell membrane is crucial to induce early endosomes maturation. In particular, evidences suggest that the N-terminal regulator of chromosome condensation 1 like domain (RLD) is necessary for membrane association thanks to its affinity to phosphoinositides, membrane lipids involved in the regulation of several signaling processes. Interestingly, this domain showed affinity towards phosphatidylinositol 3-phosphate [PI(3)P], which is highly expressed in endosomes membrane. However, Alsin structure has not been experimentally resolved yet and molecular mechanisms associated with its biological functions are mostly unknown. In this work, Alsin RLD has been investigated through computational molecular modeling techniques to analyze its conformational dynamics and obtain a representative 3D model of this domain. Moreover, a putative phosphoinositide binding site has been proposed and PI(3)P interaction mechanism studied. Results highlight the substantial conformational stability of Alsin RLD secondary structure and suggest the role of one highly flexible region in the phosphoinositides selectivity of this domain

Prediction of Protein–Protein Interactions Between Alsin DH/PH and Rac1 and Resulting Protein Dynamics

Alsin is a protein of 1,657 amino acids known for its crucial role in vesicular trafficking in neurons thanks to its ability to interact with two guanosine triphosphatases, Rac1 and Rab5. Evidence suggests that Rac1 can bind Alsin central region, composed by a Dbl Homology (DH) domain followed by a Pleckstrin Homology (PH) domain, leading to Alsin relocalization. However, Alsin three-dimensional structure and its relationship with known biological functions of this protein are still unknown. In this work, a homology model of the Alsin DH/PH domain was developed and studied through molecular dynamics both in the presence and in the absence of its binding partner, Rac1. Due to different conformations of DH domain, the presence of Rac1 seems to stabilize an open state of the protein, while the absence of its binding partner results in closed conformations. Furthermore, Rac1 interaction was able to reduce the fluctuations in the second conserved region of DH motif, which may be involved in the formation of a homodimer. Moreover, the dynamics of DH/PH was described through a Markov State Model to study the pathways linking the open and closed states. In conclusion, this work provided an all-atom model for the DH/PH domain of Alsin protein; moreover, molecular dynamics investigations suggested underlying molecular mechanisms in the signal transduction between Rac1 and Alsin, providing the basis for a deeper understanding of the whole structure–function relationship for Alsin protein

“La fine della crescita e le sfide ecologiche alla democrazia”

Abstract: In questo contributo ci proponiamo di indagare il legame tra istituzioni democratiche e crescita economica in una prospettiva socio-storica. Da un punto di vista storico le democrazie occidentali (Europa e Nord America) hanno preso forma e si sono sviluppate nel corso del XX secolo in profonda simbiosi con l'economia di crescita capitalistica, al punto che oggi è molto difficile concepire molte delle istituzioni, del funzionamento e delle dinamiche delle democrazie liberali al di fuori di questo contesto e di questo legame simbiotico. Nell'analizzare questo legame si cercherà di prendere in considerazione tre successive prospettive: il fondamento storico-genealogico, la costituzione di un consenso di base verso le democrazie liberali e la sostituzione del cittadino con il consumatore nello spazio pubblico. Nella seconda parte di questo lavoro, con riferimento al momento presente e alle prospettive future, ci interrogheremo proprio sul possibile crollo di questo connubio tra democrazia e crescita che riteniamo non più possibile o auspicabile

Quantum paradigms in psychopathology: multiscale investigations from biomolecular qubits to the brain, and its pathological states

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Alteration of lipid bilayer mechanics by volatile anesthetics: insights from μs-long molecular dynamics simulations

Very few drugs in clinical practice feature the chemical diversity, narrow therapeutic window, unique route of administration, and reversible cognitive effects of volatile anesthetics. The correlation between their hydrophobicity and their potency and the increasing amount of evidence suggesting that anesthetics exert their action on transmembrane proteins, justifies the investigation of their effects on phospholipid bilayers at the molecular level, given the strong functional and structural link between transmembrane proteins and the surrounding lipid matrix. Molecular dynamics simulations of a model lipid bilayer in the presence of ethylene, desflurane, methoxyflurane, and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (also called F6 or 2N) at different concentrations highlight the structural consequences of VA partitioning in the lipid phase, with a decrease of lipid order and bilayer thickness, an increase in overall lipid lateral mobility and area-per-lipid, and a marked reduction in the mechanical stiffness of the membrane, that strongly correlates with the compounds' hydrophobicity

Molecular Dynamics And Binding Mechanisms Of Volatile Anesthetics Targeting Human Tubulin

Anesthesia, despite being the cornerstone of modern surgery, is to this date a biological puzzle. While scientific efforts still have not managed to frame its pharmacology in an exhaustive theoretical framework, microtubules inside neurons are thought to be essential for memory formation and consciousness. The potential ability of volatile anesthetics to alter or dampen the vibrational properties of microtubules justifies the spatiotemporal characterization of the interaction between such molecules and the tubulin dimer through the use of computational molecular modelling

In silico investigation of molecular interactions of Volatile Anesthetics: Effects on phospholipid membranes and subcellular targets

The ability of anesthetics to reversibly suppress consciousness must reside in the effects exerted onto specific molecular tar- gets. Interactions between Volatile Anesthetics and the phospholipid mem- brane as well as intracellular tubulin, were investigated using Computational Molecular Modelling, which showed rapid ligand partitioning inside the membrane and significant effects on the mechanical char- acteristics thereof, while transient binding locations have been found on the tubulin dimer

Insights into the interaction dynamics between volatile anesthetics and tubulin through computational molecular modelling

General anesthetics, able to reversibly suppress all conscious brain activity, have baffled medical science for decades, and little is known about their exact molecular mechanism of action. Given the recent scientific interest in the exploration of microtubules as putative functional targets of anesthetics, and the involvement thereof in neurodegenerative disorders, the present work focuses on the investigation of the interaction between human tubulin and four volatile anesthetics: ethylene, desflurane, halothane and methoxyflurane. Interaction sites on different tubulin isotypes are predicted through docking, along with an estimate of the binding affinity ranking. The analysis is expanded by Molecular Dynamics simulations, where the dimers are allowed to freely interact with anesthetics in the surrounding medium. This allowed for the determination of interaction hotspots on tubulin dimers, which could be linked to different functional consequences on the microtubule architecture, and confirmed the weak, Van der Waals-type interaction, occurring within hydrophobic pockets on the dimer. Both docking and MD simulations highlighted significantly weaker interactions of ethylene, consistent with its far lower potency as a general anesthetic. Overall, simulations suggest a transient interaction between anesthetics and microtubules in general anesthesia, and contact probability analysis shows interaction strengths consistent with the potencies of the four compounds