Biology subjects

Parisini, E.

Publications and source records attributed to Parisini, E..

3 recordsLinked to original sources

bioRxiv2022

A Coarse-Grained Molecular Dynamics Investigation on Spontaneous Binding of Aβ9-40 Fibril with Cholesterol-mixed DPPC Bilayer

Alzheimers disease is the most common form of dementia. Its aetiology is characterized by the misfolding and aggregation of amyloid-{beta} (A{beta}) peptides into {beta}-sheet-rich A{beta} oligomers/fibrils. Whereas experimental studies have suggested that A{beta} oligomers/fibrils interact with the cell membranes and perturb their structures and dynamics, the molecular mechanism of this interaction is still not fully understood. In the present work, we have performed a total of 120 s-long simulations to investigate the interaction between trimeric or hexameric A{beta}1-40 fibrils with either a 100% DPPC bilayer, a 70% DPPC-30% cholesterol bilayer or a 50% DPPC-50 % cholesterol bilayer. Our simulation data capture the spontaneous binding of the aqueous A{beta}1-40 fibrils with the membranes and show that the central hydrophobic amino acid cluster, the lysine residue adjacent to it and the C-terminal hydrophobic residues are all involved in the process. Moreover, our data show that while the A{beta}1-40 fibril does not bind to the 100% DPPC bilayer, its binding affinity for the membrane increases with the amount of cholesterol. Overall, our data suggest that two clusters of hydrophobic residues and one lysine help A{beta}1-40 fibrils establish stable interactions with a cholesterol-rich DPPC bilayer. These residues are likely to represent potential target regions for the design of inhibitors, thus opening new avenues in structure-based drug design against A{beta} oligomer/fibril-membrane interaction.

biochemistry↗

bioRxiv2022

Targeting triple-negative breast cancer with β1-integrin binding aptamer

Targeted therapies have increased the treatment options for triple-negative breast cancer patients. However, the paucity of targetable biomarkers and tumour heterogeneity have limited the ability of precision-guided interventions to live up to their full potential. As affinity targeting ligands, aptamers show high selectivity towards target molecules. Compared to antibodies, aptamers have lower molecular weight, increased stability during transportation, reduced immunogenicity, and increased tissue uptake. Recently, we reported the discovery of GreenB1 aptamer that is internalized in cultured triple-negative MDA-MB-231 human breast cancer cells. We show that the GreenB1 aptamer specifically targets {beta}1-integrin, a protein previously linked to breast cancer cell invasiveness and migration. Aptamer binds to {beta}1-integrin with low nanomolar affinity. GreenB1 homes in the orthotopic 4T1 triple-negative breast cancer lesions modelled in mice. Our findings suggest potential applications for the GreenB1-guided precision agents for the diagnosis and therapy of triple-negative breast cancer.

molecular biology↗

bioRxiv2022

Early Stages of Misfolding of PAP248-286 at two different pH values: An Insight from Molecular Dynamics Simulations

PAP248-286 peptides, which are highly abundant in human semen, aggregate and form amyloid fibrils that enhance HIV infection. Previous experimental studies have shown that the infection-promoting activity of PAP248-286 begins to increase well before amyloid formation takes place and that pH plays a key role in the enhancement of PAP248-286-related infection. Hence, understanding the early stages of misfolding of the PAP2482-86 peptide is crucial. To this end, we have performed 60 independent MD simulations for a total of 24 s at two different pH values (4.2 and 7.2). Our data shows that misfolding of the PAP248-286 peptide is a multistage process and that the first step of the process is a transition from an "I-shaped" structure to a "U-shaped" structure. We further observed that the structure of PAP248-286 at the two different pH values shows significantly different features. At pH 4.2, the peptide has less intra-molecular H-bonds and a reduced -helical content than at pH 7.2. Moreover, differences in intra-peptide residues contacts are also observed at the two pH values. Finally, free energy landscape analysis shows that there are more local minima in the energy surface of the peptide at pH 7.2 than at pH 4.2. Overall, the present study elucidates the early stages of misfolding of the PAP248-286 peptide at the atomic level, thus possibly opening new avenues in structure-based drug discovery against HIV infection.

biochemistry↗