Scientific Publications
All scientific publications in Area Science Park
Chirality Unlocks Sub-Terahertz Molecular Dynamics in Peptide Nanotubes
Abstract Low-frequency modes in the picosecond range play a key role in molecular recognition and biomolecular function. Here, we investigate how these dynamics at the interfaces of self-assembled peptide biomaterials relate to fine structural details of the supramolecular assembly. We resolve terahertz and mid-infrared modes in individual diphenylalanine nanotubes by nanoscale microspectroscopy, uncovering a direct correlation between supramolecular chirality, molecular arrangement, and picosecond dynamics at the nanotube-environment boundary. By combining THz and mid-IR nanoscopy with a multiscale strategy spanning single nanotubes and ensemble measurements, supported by density functional theory calculations, we access the intrinsic picosecond response of peptide assemblies beyond the limits of conventional microscopy and ensemble averaging. Heterochiral (D-L) nanotubes display sharp resonances, whereas homochiral (L-L) nanotubes exhibit a comparatively featureless sub-THz profile, revealing a clear chirality-dependent contrast. Mode assignments show that the heterochiral features are dominated by localized torsional and bending motions of phenyl rings relative to the peptide backbone. Overall, chirality-dependent THz fingerprints emerge as sensitive descriptors of peptide nanotube architecture, while low-frequency nanospectroscopy provides a route to interrogate biomaterial interfaces under biologically relevant conditions. Authors Rajat Kumar, Erica Scarel, Andrea Perucchi, Lisa Vaccari, Prasanta Kumar Datta, Francesco D’amico, Paola Di Pietro, Silvia Marchesan, Federica Piccirilli Journal ChemrXiv Publication date 11/03/2026 Consult the publication
A comprehensive framework for solution space exploration in community detection
Abstract: Community detection algorithms are essential tools for understanding complex networks, yet their results often vary between runs and are affected by node input order and the presence of outliers, undermining reproducibility and interpretation. This paper addresses these issues by introducing a framework for systematic exploration of the solution space, obtained through repeated runs of a given algorithm with permuted node orders. A Bayesian model assesses convergence, estimates solution probabilities, and provides a defensible stopping rule that balances accuracy and computational cost. Building on this process, we propose a taxonomy of solution spaces that offers clear diagnostics of partition reliability across algorithms and a shared vocabulary for interpretation. Applied to a real-world network, the approach shows that different algorithms produce various types of solution space, highlighting the importance of systematic exploration of the solutions before drawing scientific conclusions. Authors Fabio Morea, Domenico de Stefano Journal Scientific Reports Pubblication date 31/10/2025 Consult the pubblication
Ultrafast Intermolecular Dynamics of Nanoconfined Water in Swollen Lipid Cubic Mesophases
Abstract Understanding the structure and dynamics of the hydrogen-bond network ofwater in topologically distinct swollen lipidic mesophases, is fundamental fortheir application in biomedical, pharmaceutical, and food science fields. Here,a positive and non-linear correlation between water hydrogen-bond dynamicsand interfacial water population is uncovered in inverse bicontinuous swollenmesophases across an extended temperature range (298–340 K). Particularly,small-angle X-ray scattering determines the mesophase’s structural features,uncovering a temperature-driven re-entrant phenomenon (reappearance) ofPn̄ 3m phase upon heating. This topologically rich environment, however, hasno detectable impact on the temperature dependence of the intermolecularmodes of water, as revealed by terahertz absorption spectroscopy. Specifically,these modes show distinct dynamics: the stretching mode exhibits longerlifetimes than the libration mode, yet with a higher temperature-dependence,with approximately two-fold lower Arrhenius activation energies. In contrast,both stretching and libration modes exhibit a monotonic decrease in lifetimewith increasing temperature, due to the increasing disruption of thehydrogen-bond network. Atomistic molecular dynamics simulations enablethe quantification of interfacial water population, which shows a positivecorrelation with intermolecular lifetimes in a nonlinear manner, revealing anon-additive coupling between interfacial water population and waterhydrogen-bond network dynamics within these systems. Authors Eva Zunzunegui-Bru, Serena Rosa Alfarano, Patrick Züblin, Laura Baraldi,Hendrik Vondracek, Federica Piccirilli, Lisa Vaccari, and Raffaele Mezzenga Journal Small Publication date 03/10/2025 Consult the publication
Rational optimization of D3R/GSK-3β dual target-directed ligands as potential treatment for bipolar disorder: Design, synthesis, X-ray crystallography, molecular dynamics simulations, in vitro ADME, and in vivo pharmacokinetic studies
Abstract Bipolar disorder is a complex neuropsychiatric condition with a significant unmet medical need, as current treatments lack disease-modifying properties and multimodal therapeutic effects. To overcome the limitations of single-target drugs, we designed dual-target ligands that combine partial agonism at the dopamine D3 receptor (D3R) with inhibition of glycogen synthase kinase-3β (GSK-3β). We previously identified ARN24161 (1) as a promising prototype, demonstrating partial agonism at D3R (EC50 = 10.1 nM, % Eff. = 26.3) and GSK-3β inhibition (IC50 = 561 nM). However, its drug-like properties remained suboptimal. To optimize this compound, we initiated a multidisciplinary refinement campaign, leveraging computational modeling and crystallographic data to fine-tune the balance between D3R and GSK-3β activity, reduce P-glycoprotein (P-gp) affinity, and improve the pharmacokinetic profile. This effort led to the identification of ARN25297 (5), a moderately balanced dual-target ligand that exhibits partial agonism at D3R (EC50 = 13.1 nM, % Eff. = 17.1) and potent GSK-3β inhibition (IC50 = 47.0 nM). Notably, ARN25657 (16) emerged as the most well-balanced candidate, demonstrating enhanced D3R partial agonism (EC50 = 15.2 nM, % Eff. = 37.7) alongside strong GSK-3β inhibition (IC50 = 19.3 nM). Compound 16 also exhibited the lowest P-gp inhibition and significant improvements in in vitro ADME properties compared to prototype 1, while maintaining a balanced dual target profile. Although the PK profile of 16 remained comparable to that of prototype 1, these findings lay the groundwork for further lead optimization and structural refinement, driving future in vivo proof-of-concept toward innovative therapeutic strategies for bipolar disorder and related neuropsychiatric conditions. Authors RMC Di Martino, D Russo, I Penna, Andrea Dalle Vedove, R Spabnuolo, G Ottonello, M Summa, J Desantis, A Valeri, L Pruccoli, SK Tripathi, A Tarozzi, Paola Storici, S Girotto, R Bertorelli, A Armirotti, G Cruciani, T Bandiera, A Cavalli, G Bottegoni Journal European Journal of Medicinal Chemistry Publication date 25/06/2025 Consult the publication
FL30: an epidermal growth factor kinase inhibitor overcoming T790M and C797S mutations through unique conformational modulation mechanism
Abstract Tyrosine kinase inhibitors (TKIs) targeting the oncogene Epidermal Growth Factor Receptor (EGFR) are widely used in the treatment of non-small cell lung cancer (NSCLC). In this context, the introduction of fourth-generation TKIs has significantly advanced targeted therapy for T790M and C797S EGFR mutations. Current therapeutic strategies are increasingly focusing on the design of orthoallosteric TKIs, which have shown promise in stabilizing the inactive conformation of mutated EGFR. In this context, we report the discovery of FL30, a small molecule with a flavone core that exhibits nanomolar potency against the EGFR-L858R/T790M mutation, even in the presence of the C797S mutation. The IC50 comparable to the Osimertinib – one of the most renowned EGFR-TKIs – emphasizes the remarkable success of the design approach. In NSCLC models, FL30 effectively inhibits cancer growth and EGFR phosphorylation selectively in cells with the EGFR mutations. Kinetic studies, molecular modeling, and Plasmon Internal Reflection Surface-Enhanced Infrared Absorption (PIR-SEIRA) microscopy suggests that FL30 binds to the orthosteric site while inducing the transition of the mutant EGFR toward an inactive-like state. These findings highlight FL30’s potential for further optimization and propose a novel approach for developing targeted therapies that combine orthosteric binding with allosteric modulation. Authors Elena Romagnoli, Emiliano Laudadio, Giovanna Mobbili, Leonardo Sorci, Giovanni Birarda, Federica Piccirilli, Lisa Vaccari, Hendrik Vondracek, Brenad Romaldi, Massimo Marcaccio, Paola Storici, Marta Semrau, Roberta Galeazzi, Andrea Toma, Vincenzo Aglieri, Pierluigi Stipa, Tatiana Armeni, Cristina Minnelli Journal International Journal of Biological Macromolecules Publication date 21/06/2025 Consult the publication
Broadband terahertz signatures and vibrations of Phe–Phe peptide and its fibrils
Abstract In recent years, peptide-based nanomaterials have gained significant attention in drug discovery due to their biocompatibility and promising functionality in biophysical processes. This current study employs terahertz (THz) spectroscopy and density functional theory (DFT) to investigate the vibrational properties of the phenylalanine dipeptide (Phe–Phe), a building block with notable self-assembling properties and potential applications in drug delivery and nanostructured biomaterials. The dynamics of proteins and biomolecules occurring on the picosecond timescale can be probed by THz spectroscopy and is closely related to their functionality. Here, we investigate the low-frequency vibrational modes of Phe–Phe under two different conditions, as crystalline commercial powder and post-self-assembled powder, in the 0.2–4 THz range. The refractive index of pure Phe–Phe, as evaluated from THz spectroscopy, is approximately 1.47, and the THz absorption peaks are observed at 0.55, 0.83, 1.13, 1.40, 1.68, 2.18, 2.71, 3.00, and 3.33 THz. Potential energy distribution (PED) analysis provides a detailed assignment of the observed modes and identifies characteristic vibrational features. The novel thin bi-layer approach for sample preparation employed here proved to be effective in terms of signal-to-noise ratio and in eliminating artifacts possibly originating from the host material. This combined experimental–computational approach not only offers valuable insights into the conformational flexibility and self-assembly potential of Phe–Phe, but also underscores the efficacy of THz spectroscopy and DFT analysis for studying the vibrational properties of peptides, with implications for biophysics, nanotechnology, and biochemistry. Moreover, this study highlights the impact of intermolecular interactions on the vibrational spectra by comparing crystalline powder and self-assembled peptide powder. Authors Rajat Kumar, Federica Piccirilli, Paola Di Pietro, Johannes Schmidt, Giovanni Birarda, Lisa Vaccari, Andrea Perucchi, Prasanta Kumar Datta Journal Analyst Publication date 24/04/2025 Consult the publication
Eco-friendly NaCl glycerol-based deep eutectic electrolyte for high-voltage electrochemical double layer capacitor
Abstract Herein, we propose eco-friendly electrolytes based on sodium chloride as a hydrogen bond acceptor and glycerol as a hydrogen bond donor, as alternatives to toxic, flammable and unsustainable electrolytes commonly used in electrochemical energy storage systems. By means of an in-depth multi-technique investigation, including Raman and FT-FIR spectroscopy, of the formulated electrolytes, we point out the effect of the structuring of the system on the transport and electrochemical properties. The 1 : 10 molar ratio mixture proves to be a deep eutectic solvent (DES), showing good room temperature ionic conductivity (0.186 mS cm−1) and electrochemical stability (≈3 V). When implemented as electrolyte in an activated-carbon electrochemical double layer capacitor, this DES exhibits superior performance compared to mixtures with different molar ratio and those containing ethylene glycol as the hydrogen bond donor, with a high operational voltage (2.6 V), a specific capacitance of 14.1 F g−1, and a remarkable cycling stability. These findings highlight the potential of glycerol-based DESs as alternative electrolytes for sustainable electrochemical energy storage applications. Authors Daniele Motta, Alessandro Damin, Hamideh Darjazi, Stefano Nejrotti, Federica Piccirilli, Giovanni Birarda, Claudia Barolo, Claudio Gerbaldi, Giuseppe Antonio Elia, Matteo Bonomo Journal Green Chemistry Publication date 31/03/2025 Consult the publication
Cobalt recycling patents dataset selected using ‘green’ classification codes: Focus on the nickel manganese cobalt (NMC) batteries recycling
Abstract The Critical Raw Materials Act has been emanated to address perceived risks around supply chains for critical raw materials in light of expected demand growth. Cobalt is one of the critical raw materials for the EU: it plays a central role in transition to a low-carbon economy and is crucial for batteries powering electric vehicles. The cobalt industry is important not only because of the green transition, it also creates employment opportunities as Europe is the third largest region for total global cobalt value chain employment. The global market for battery electric vehicles (BEVs) is continuously increasing which results in higher material demand for the production of Li-ion batteries (LIBs). Especially Lithium nickel manganese cobalt (NMC) batteries are one of the leading types of batteries deployed on BEVs and recovering of materials from used batteries for producing new battery materials may mitigate the material supply risk. The present survey concerns the creation and comparison of two datasets of patents concerning Cobalt recycling, respectively achieved without (dataset 1) and with (dataset 2) the addition of one specific ‘green’ CPC classification code to a huge list of classification codes concerning recycling. Namely, the CPC Y02P10/20 determines a significant improvement on the exhaustivity of the search regarding Cobalt recycling in dataset 2, on the other hand it might also generate issues evidenced by a subsequent selection of those records in principle focused on the recovery of NMC batteries and characterized by several false positives. Therefore, a refinement strategy is recommended, to make the accuracy of the NMC dataset comparable to that characterizing the NMC results from dataset 1 achieved without any refinement. Author Riccardo Priore Journal Data in Brief, March 2024, 105519 Date Available online 13/03/2024 Consult the paper
A supported lipid bilayer to model solid-ordered membrane domains
Abstract Membrane models are widely used to mimic the behaviour of native plasma membranes and to simulate interactions occurring at their interface. Such models can be built up with different molecular compositions, ranging from single phospholipids to more complex, heterogeneous mixtures of phospho- and sphingo-lipids, possibly enriched with cholesterol and proteins. In particular, mixing different lipids and cholesterol is instrumental to promote the formation of phase-separated, ordered domains, which resemble the structure of lipid rafts, specialized functional domains of real membranes. According to the specific lipid composition, physical characteristics of the rafts can be tuned, such as fluidity, strongly related to membrane biological activity. Here, we introduce a novel three-component membrane model constituted by the mixing of a saturated phospholipid, 1,2-dimyristoyl-sn–glycero-3-phosphocholine (DMPC), sphingomyelin and cholesterol to mimic the presence of solid ordered rafts and to study their behaviour. Differential scanning calorimetry, neutron reflectometry, and atomic force microscopy were synergistically applied to gain information on the membrane’s transverse and lateral organization, as well as on its thermotropic behaviour. The membrane model benefits from the use of DMPC, a lipid (i) characterized by an accessible transition temperature; (ii) saturated; (iii) fluid at physiological temperature and (iv) commercially available in both protiated and deuterated forms. The proposed model, along with the wide range of biophysical techniques employed, constitutes an ideal system to study the molecular mechanisms and the physical properties that govern membrane functions, such as molecular signalling and membrane trafficking. Authors Sally Helmy, Paola Brocca, Alexandros Koutsioubas, Stephen C.L. Hall, Luca Puricelli, Pietro Parisse, Loredana Casalis, Valeria Rondelli Journal Journal of Colloid and Interface Science Publication Date 14/03/2025 Consult the publication
Co-assembled supramolecular hydrogels: nano-IR sheds light on tripeptide assemblies
Abstract Supramolecular hydrogels composed of self-assembling short peptides are gaining momentum for enzyme mimicry. In particular, multicomponent systems that feature similar peptides with a self-assembling motif (e.g., Phe–Phe) and catalytic residues (e.g., His, Asp) offer a convenient approach to organize in space, functional residues that typically occur at enzymatic active sites. However, characterisation of these systems, and especially understanding whether the different peptides co-assemble or self-sort, is not trivial. In this work, we study two-component hydrogels composed of similar tripeptides and describe how nano-IR can reveal important details of their packing, thus demonstrating it to be a useful technique to characterise multicomponent, nanostructured gels. Authors Paola Alletto, Ana M. Garcia, Federica Piccirilli, Silvia Marchesan Journal Faraday Discussions Publication date 21/02/2025 Consult the publication
CO2 and Temperature Induced Switching of a Flexible Metal–Organic Framework with Surface-Mounted Nanoparticles
Abstract Within the material family of metal–organic frameworks (MOFs) the subclass of flexible MOFs (flexMOFs) has attracted great attention, showing structural flexibility as a response to external stimuli such as guest adsorption, temperature, and pressure. Hybrid composites like nanoparticle (NP) loaded flexible MOFs, which stand to potentially combine advantageous properties of both are yet largely unexplored. Here the synthesis of flexMOFs with surface mounted nanoparticles, e. g. NP@Zn2(BME-bdc)2dabco composites (NP = Pt and SiO2 nanoparticles, BME-bdc2− = 2,5-bismethoxyethoxy-1,4-benzenedicarboxylate, dabco = 1,4-diazabicyclo[2.2.2]octane) is reported, studying the impact of nanoparticles on the stimulus-responsiveness of a flexMOF. It is shown that CO2 physisorption triggered flexibility of the MOF is retained and reversible for all NP@flexMOF composites. Additionally, it is observed that NPs stabilize the large pore state of the MOF, slightly increasing and shifting the switching pressure window. This effect is also observed during temperature-induced switching but Pt@flexMOF composites partially lose long-range order during the reversion to their narrow pore state, while attached SiO2 NPs allow for a fully reversible transition. These findings suggest that the total exerted material strain triggering the switching is heavily dependent on NP size and the applied stimulus and that guest-induced switchability can be fully realized in NP@flexMOF hybrid materials. Authors Jan Berger, Stephanie Terruzzi, Hana Bunzen, Filippo Ballerini, Marco Vandone, Marcello Marelli, Luca Braglia, Roland A. Fischer, Valentina Colombo, Gregor Kieslich Journal Small Date 07/01/2025 Consult the paper
Innovation in rare earths recycling: a quantitative and qualitative analysis of patent data
Abstract Rare earth elements (REE) are currently essential enablers of the digital and decarbonization transition. However, their supply chain is highly concentrated and their extraction has a high environmental impact. Circular economy solutions could provide a double benefit, reducing supply risk for import-dependent countries and mitigating the impacts of REE mining. This article focuses on REE recycling and provides a comprehensive global overview of innovation dynamics in this sector using patent data. We propose a two-step patent search methodology to identify REE recycling patents, based on the OECD ENV-TECH classification for green technologies and keyword occurrence. We then develop a set of quantitative and qualitative metrics to explore innovation dynamics at the country, applicant and technology type level. China clearly emerges as the most attractive market for REE recycling patents and Chinese universities as the most active applicants worldwide. Conversely, patent applications in all other countries showed stagnating trends over the last decade. In particular, Europe has a lower number of both patent applications and patents developed compared to the US and Japan. However, patent quality indicators show a very different picture: US and Japanese applicants, who appear to be at the technological forefront, receive more citations and are more oriented towards protecting their inventions internationally. Our analysis therefore highlights the importance of considering both quantitative and qualitative patent metrics when examining innovation trends in REE recycling. We discuss the determinants of these observed phenomena, draw policy implications – particularly for REE import-dependent countries – and propose avenues for future research at the intersection of CRM, the circular economy, and innovation studies. Authors Riccardo Priore , Marco Compagnoni , Marinella Favot Journal Resources Policy Volume 102, March 2025, 105519 Date Available online 24/02/2025 Consult the paper