Biology subjects

Bochicchio, D.

Publications and source records attributed to Bochicchio, D..

5 recordsLinked to original sources

bioRxiv2026

The monomeric conformational ensembles of Aβ40 and Aβ42 encode their differential amyloid aggregation propensity

A{beta}40 and A{beta}42 peptides differ by just two C-terminal residues, yet they display strikingly different aggregation and toxicity profiles. Whether this distinction is already encoded at the monomer level is still under debate. Here, we combine extensive all-atom simulations in explicit solvent, well-tempered metadynamics, and a tailored consensus cluster analysis to compare the monomeric ensembles of the two isoforms under identical conditions. Both peptides populate broad, coil-like conformational distributions; however, A{beta}42 shows systematically higher {beta}-structure propensity, especially in the C-terminal region, and samples more extended conformations with higher hydrophobic exposure compared to A{beta}40. These results support a mechanistic link between sequence-encoded monomer conformational preferences and the differential amyloidogenicity of the two isoforms, highlighting monomer-level determinants of A{beta}42s distinct aggregation behavior.

biophysics↗

bioRxiv2025

Hot cue: Physiologically controlled release from an in situ forming liposomal depot

Poor treatment adherence, often referred to as the "silent epidemic", is a growing global issue that significantly contributes to preventable illness, premature death, and rising healthcare costs. Among compliance-enhancing strategies, controlled-release depots designed for intermediate treatment cycles represent a suitable approach, particularly in contexts where frequent dosing is impractical. Current long-acting injectable formulations, though, are often hindered by challenges in injectability, delayed onset, and complex manufacturing. Here, we present a thermoresponsive, in situ forming liposomal depot (TILD) designed to modulate the release of membrane-associated drugs following subcutaneous administration. Using buprenorphine as a model analgesic, we demonstrate that TILD responds to subcutaneous divalent cations with immediate surface-drug release and to body temperature with sustained diffusion through a fluidized bilayer. Molecular simulations guided the system design, and structural and colloidal characterizations validated its responsiveness to physiological cues. In vivo, TILD formed stable depots and maintained therapeutic drug levels for up to four days in both rats and Beagle dogs. Pharmacodynamics studies in rats confirmed the delivery of prolonged analgesia.

pharmacology and toxicology↗

bioRxiv2023

Nanoparticle-induced biomembrane fusion: unraveling the effect of core size on stalk formation

Membrane fusion in vitro is a strategy to load model or cell-derived vesicles with proteins, drugs, and genetic materials for theranostic applications. It is thus crucial to develop strategies to control the fusion process, also through synthetic fusogenic agents. Ligand-protected, membrane-penetrating gold nanoparticles (Au NPs) can facilitate membrane fusion, but the molecular mechanisms remain unresolved. Here, we tackle NP-induced stalk formation using a coarse-grained Molecular Dynamics approach and enhanced sampling techniques. We show that smaller (2 nm in diameter) NPs lead to a lower free energy barrier and higher stalk stability than larger NPs (4 nm). We demonstrate that this difference is due to a different ligand conformational freedom, which in turn depends on the Au core curvature. Our study provides precious insights into the mechanisms underlying NP-mediated membrane fusion, while our computational approach is general and applicable to studying stalk formation caused by other fusogenic agents. TOC GRAPHICS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/541080v1_ufig1.gif" ALT="Figure 1"> View larger version (93K): org.highwire.dtl.DTLVardef@137598forg.highwire.dtl.DTLVardef@d8c93eorg.highwire.dtl.DTLVardef@842de2org.highwire.dtl.DTLVardef@1e08f44_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Cholesterol-containing liposomes decorated with Au nanoparticles as minimal tunable fusion machinery

Membrane fusion is essential for the basal functionality of eukaryotic cells. In physiological conditions, fusion events are regulated by a wide range of specialized proteins, as well as by a finely tuned local lipid composition and ionic environment. SNARE proteins, for example, provide the mechanical energy necessary to achieve vesicle fusion in neuromediator release, and their action is assisted by other soluble proteins, membrane cholesterol, and calcium ions. Similar cooperative effects must be explored when considering synthetic approaches to achieve controlled and selective membrane fusion. Here we show that liposomes decorated with amphiphilic Au nanoparticles (AuLips) can act as minimal tunable fusion machinery. AuLips fusion is triggered by divalent ions, while the number of fusion events dramatically depends on, and can be finely tuned by, the liposome cholesterol content. Our results, obtained via a combination of experimental (Quartz-Crystal-Microbalance with Dissipation monitoring, Fluorescence assays, Small-Angle X-ray Scattering) and computational techniques (Molecular Dynamics with coarse-grained resolution), reveal new mechanistic details on the fusogenic activity of amphiphilic Au nanoparticles in synergy with membrane cholesterol, and demonstrate the ability of these synthetic nanomaterials to induce fusion regardless of the divalent ion used (Ca2+ or Mg2+). This evidence provides a novel contribution to the development of new artificial fusogenic agents for next-generation biomedical applications that require tight control of the rate of fusion events (e.g., targeted drug delivery).

biophysics↗

bioRxiv2021

Ions and lipids drive aggregation of surface-functionalized gold nanoparticles on lipid membranes

The control of the aggregation of biomedical nanoparticles (NP) in physiological conditions is crucial as clustering may change completely the way they interact with the biological environment. Here we show that Au nanoparticles, functionalized by an anionic, amphiphilic shell, spontaneously aggregate in fluid zwitterionic lipid bilayers. We use Molecular Dynamics and enhanced sampling techniques to disentangle the short-range and long-range driving forces of aggregation. At short inter-particle distances, ion-mediated, charge-charge interactions (ion bridging) stabilize the formation of large NP aggregates, as confirmed by cryo-electron microscopy. Lipid depletion and membrane curvature are the main membrane deformations driving long-range NP-NP attraction. Ion bridging, lipid depletion, and membrane curvature stem from the configurational flexibility of the nanoparticle shell. Our simulations show, more in general, that the aggregation of same-charge membrane inclusions can be expected as a result of intrinsically nanoscale effects taking place at the NP-NP and NP-bilayer soft interfaces.

biophysics↗