Biology subjects

Rocchia, W.

Publications and source records attributed to Rocchia, W..

5 recordsLinked to original sources

bioRxiv2026

Branching Suppresses Self-Aggregation while Preserving Membrane Association in SET-M33: An Atomistic Molecular Dynamics Study

Branched antimicrobial peptides offer a promising strategy for improving the stability and activity of membrane-active peptides, but how branching alters self-association and membrane binding remains unclear. We used all-atom molecular dynamics simulations to compare tetra-branched SET-M33 with its linear branch sequence Q33 (KKIRVRLSA) in water and at an anionic bacterial-membrane model, to do this, systems containing equivalent numbers of Q33 sequence units were simulated. Q33 formed dimers and higher-order oligomers, particularly at the membrane interface and under hydration-tuned enhanced sampling. In contrast, SET-M33 remained more dispersed, as the branched scaffold and its high cationic charge limited peptide-peptide association while allowing multivalent membrane binding. Both architectures associated rapidly with the bilayer but remained predominantly surface-bound, without persistent pore formation or complete insertion. Q33 showed stronger membrane-induced helical stabilization, whereas SET-M33 retained a more heterogeneous conformational ensemble. Overall, branching primarily altered lateral peptide organization while preserving close membrane association, suppressing uncontrolled self-aggregation and providing an atomistic rationale for the distinct behavior of SET-M33 relative to Q33.

biophysics↗

bioRxiv2025

Synergistic Effects of pH and Temperature on Dengue VirusEnvelope Dimers: Insights from Microsecond MolecularDynamics Simulations

Dengue pathogenesis depends on a conformational rearrangement of the envelope (E) glycoprotein induced by low pH; however, how pH and temperature cooperate to destabilize its prefusion dimeric state, a fundamental step that enables the formation of the fusion-active trimer, remains unclear. Here, we investigate this synergy for Dengue serotypes of greatest medical relevance, DENV-2 and DENV-3. All-atom molecular dynamics simulations were performed on the microsecond scale, at 28 {degrees}C, 37 {degrees}C, and 40 {degrees}C under pH 5-7, using CHARMM36m force fields. The increase in temperature from 28 {degrees}C to 37 {degrees}C doubled the conformational space explored at neutral pH and weakened both dimers through the reduction or loss of the interaction network along the dimeric interface. Acidification amplified this effect in a serotype-specific manner: DENV-2 required pH 5, while DENV-3 responded at pH 6. Distance and principal component analyses revealed an asymmetric dissociation route, termed the "compensatory embrace", in which retraction of Domains I and III in one monomer is balanced by advancement of its partner on the opposite side, temporarily preserving the number of inter-subunit contacts. Structural analyses highlighted the difference in histidine distribution between the serotypes. These results outline hierarchical physicochemical triggers that convert the dimer into fusion-competent monomers. Targeting the interfacial interaction network or reinforcing the "compensatory embrace" to prevent completion of dissociation offers new perspectives for broad-spectrum antivirals and immunogen design, underscoring the value of long-timescale molecular dynamics in drug discovery.

biophysics↗

bioRxiv2023

Theoretical Analysis of Divalent Cation Effects on Aptamer Recognition of Neurotransmitter Targets

Aptamer-based sensing of small molecules such as dopamine and serotonin in the brain, requires characterization of the specific aptamer sequences in solutions mimicking the in vivo environment with physiological ionic concentrations. In particular, divalent cations (Mg2+ and Ca2+) present in brain fluid, have been shown to affect the conformational dynamics of aptamers upon target recognition. Thus, for biosensors that transduce aptamer structure switching as the signal response, it is critical to interrogate the influence of divalent cations on each unique aptamer sequence. Herein, we demonstrate the potential of molecular dynamics (MD) simulations to predict the behaviour of dopamine and serotonin aptamers on sensor surfaces. The simulations enable molecular-level visualization of aptamer conformational changes that, in some cases, are significantly influenced by divalent cations. The correlations of theoretical simulations with experimental findings validate the potential for MD simulations to predict aptamer-specific behaviors on biosensors.

neuroscience↗

bioRxiv2021

RAD51 nuclear recruitment and inhibition towards innovative strategies against pancreatic cancer

RAD51, a key player in the homologous recombination (HR) mechanism, is a critical protein to preserve genomic stability. BRCA2, upon DNA damage, promotes RAD51 fibrils disassembly and its nuclear recruitment. Here, we use BRC4, a peptide derived from the fourth BRC repeat of BRCA2; BRC4 induces RAD51 defibrillation through a domino effect, eroding fibrils from their termini, and yielding monomeric RAD51. The congruence among several techniques (static and dynamic light scattering, negative staining transmission electron microscopy (TEM), and microscale thermophoresis) allows an accurate estimation of the kinetic and thermodynamic parameters of this process. BRC4 lacks, however, a nuclear localization sequence; therefore, it cannot transport RAD51 into the nucleus, thus behaving as a RAD51 inhibitor. Cellular assays (BxPC-3, pancreatic cancer cells) indeed show that BRC4 efficiently inhibits HR and enhances the cytotoxic effect of cisplatin, a DNA-damaging drug. The present study sheds further light on the complexity of the HR pathway, paving the way for designing peptide and small organic molecule inhibitors of RAD51 as innovative anticancer and chemo/radiosensitizer compounds.

biophysics↗

bioRxiv2019

Electrostatics and Solvation: Essential Determinants of Chromatin Compaction

Chromatin compaction is a process of fundamental importance in Biology, as it greatly influences cellular function and gene expression. The dynamics of compaction is determined by the interactions between DNA and histones, which are mainly mechanical and electrostatic. The high charge of DNA makes electrostatics extremely important for chromatin topology and dynamics. Besides their mechanical and steric role in the chromatin fibre, linker DNA length and linker histone presence and binding position also bear great electrostatic consequences. Electrostatics in chromatin is also indirectly linked to the DNA sequence: the presence of high-curvature AT-rich segments in DNA can cause conformational variations with electrostatic repercussions, attesting to the fact that the role of DNA is both structural and electrostatic. Electrostatics in this system has been analysed by extensively examining at the computational level the repercussions of varying ionic concentration, using all-atom, coarse-grained, and continuum models. There have been some tentative attempts to describe the force fields governing chromatin conformational changes and the energy landscapes of these transitions, but the intricacy of the system has hampered reaching a consensus. Chromatin compaction is a very complex issue, depending on many factors and spanning orders of magnitude in space and time in its dynamics. Therefore, comparison and complementation of theoretical models with experimental results is fundamental. Here, we present existing approaches to analyse electrostatics in chromatin and the different points of view from which this issue is treated. We pay particular attention to solvation, often overlooked in chromatin studies. We also present some numerical results on the solvation of nucleosome core particles. We discuss experimental techniques that have been combined with computational approaches and present some related experimental data such as the Z-potential of nucleosomes at varying ionic concentrations. Finally, we discuss how these observations support the importance of electrostatics and solvation in chromatin models.\n\nSIGNIFICANCEThis work explores the determinants of chromatin compaction, focusing on the importance of electrostatic interactions and solvation. Chromatin compaction is an intrinsically multiscale issue, since processes concerning chromatin occur on a wide range of spatial and temporal scales. Since DNA is a highly charged macromolecule, electrostatic interactions are extremely significant for chromatin compaction, an effect examined in this work from many angles, such as the importance of ionic concentration and different ionic types, DNA-protein interactions, and solvation. Solvation is often overlooked in chromatin studies, especially in coarse-grained models, where the nucleosome core, the building block of the chromatin fibre, is represented as a rigid body, even though it has been observed that solvation influences chromatin even at the base-pair level.

biophysics↗