Highlighting the effect of amyloid beta assemblies on the mechanical properties and conformational stability of cell membrane

Alzheimer disease (AD) is the most common cause of dementia, characterized by a progressive decline in cognitive function due to the abnormal aggregation and deposition of Amyloid beta (Aβ) fibrils in the brain of patients. In this context, the molecular mechanisms of protein misfolding and aggregation that are known to induce significant biophysical alterations in cells, including destabilization of plasma membranes, remain partially unclear. Physical interaction between the Aβ assemblies and the membrane leads to the disruption of the cell membrane in multiple ways including, surface carpeting, generation of transmembrane channels and detergent-like membrane dissolution. Understanding the impact of amyloidogenic protein in different stages of aggregation with the plasma membrane, plays a crucial role to fully elucidate the pathological mechanisms of AD. Within this framework, computer simulations represent a powerful tool able to shed lights on the interactions governing the structural influence of Aβ proteins on biological membrane. In this study, molecular dynamics (MD) simulations have been performed in order to characterize how POPC bilayer conformational and mechanical properties are affected by the interaction with Aβ11-42 peptide, oligomer and fibril

Molecular and Coarse-Grained Modeling to Characterize and Optimize Dendrimer-Based Nanocarriers for Short Interfering RNA Delivery

Dendrimer nanocarriers are unique hyper-branched polymers with biomolecule-like properties, representing a promising prospect as a nucleic acid delivery system. The design of effective dendrimer-based gene carriers requires considering several parameters, such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity. In detail, the rational design of the dendrimer surface chemistry has been ascertained to play a crucial role on the efficiency of interaction with nucleic acids. Within this framework, advances in the field of organic chemistry have allowed us to design dendrimers with even small difference in the chemical structure of their surface terminals. In this study, we have selected two different cationic phosphorus dendrimers of generation 3 functionalized, respectively, with pyrrolidinium (DP) and morpholinium (DM) surface groups, which have demonstrated promising potential for short interfering RNA (siRNA) delivery. Despite DP and DM differing only for one atom in their chemical structure, in vitro and in vivo experiments have highlighted several differences between them in terms of siRNA complexation properties. In this context, we have employed coarse-grained molecular dynamics simulation techniques to shed light on the supramolecular characteristics of dendrimer-siRNA complexation, the so-called dendriplex formations. Our data provide important information on self-assembly dynamics driven by surface chemistry and competition mechanisms

The impact of natural compounds on s-shaped aβ42 fibril: From molecular docking to biophysical characterization

The pursuit for effective strategies inhibiting the amyloidogenic process in neurodegenerative disorders, such as Alzheimer’s disease (AD), remains one of the main unsolved issues, and only a few drugs have demonstrated to delay the degeneration of the cognitive system. Moreover, most therapies induce severe side effects and are not effective at all stages of the illness. The need to find novel and reliable drugs appears therefore of primary importance. In this context, natural compounds have shown interesting beneficial effects on the onset and progression of neurodegenerative diseases, exhibiting a great inhibitory activity on the formation of amyloid aggregates and proving to be effective in many preclinical and clinical studies. However, their inhibitory mechanism is still unclear. In this work, ensemble docking and molecular dynamics simulations on S-shaped Aβ42 fibrils have been carried out to evaluate the influence of several natural compounds on amyloid conformational behaviour. A deep understanding of the interaction mechanisms between natural compounds and Aβ aggregates may play a key role to pave the way for design, discovery and optimization strategies toward an efficient destabilization of toxic amyloid assemblies

TAT-RasGAP_317-326 kills cells by targeting inner-leaflet-enriched phospholipids.

TAT-RasGAP <sub>317-326</sub> is a cell-penetrating peptide-based construct with anticancer and antimicrobial activities. This peptide kills a subset of cancer cells in a manner that does not involve known programmed cell death pathways. Here we have elucidated the mode of action allowing TAT-RasGAP <sub>317-326</sub> to kill cells. This peptide binds and disrupts artificial membranes containing lipids typically enriched in the inner leaflet of the plasma membrane, such as phosphatidylinositol-bisphosphate (PIP <sub>2</sub> ) and phosphatidylserine (PS). Decreasing the amounts of PIP <sub>2</sub> in cells renders them more resistant to TAT-RasGAP <sub>317-326</sub> , while reducing the ability of cells to repair their plasma membrane makes them more sensitive to the peptide. The W317A TAT-RasGAP <sub>317-326</sub> point mutant, known to have impaired killing activities, has reduced abilities to bind and permeabilize PIP <sub>2</sub> - and PS-containing membranes and to translocate through biomembranes, presumably because of a higher propensity to adopt an α-helical state. This work shows that TAT-RasGAP <sub>317-326</sub> kills cells via a form of necrosis that relies on the physical disruption of the plasma membrane once the peptide targets specific phospholipids found on the cytosolic side of the plasma membrane