Exploring chemistry and catalysis by biasing skewed distributions via deep learning Zhikun Zhang, GiovanniMaria Piccini Nature Communications, 2026 The automated discovery of chemical and catalytic reactions remains a major challenge in computational chemistry, particularly in complex systems where conventional methods struggle to identify optimal searching directions. Here, we propose Loxodynamics, a machine-learning-driven approach for reaction exploration via biased molecular dynamics. By leveraging the skewness of local probability distributions, Loxodynamics dynamically determines low-energy barrier directions, efficiently guiding the system toward metastable states. The core of our framework is Skewencoder, an Autoencoder augmented with a skewness-based loss function that extracts reaction coordinates from minimal sampling data. Through iterative sample-and-search cycles, the system adaptively maps the free energy surface, capturing finite-temperature effects critical to complex reactive environments. We validate our method across model potentials, gas-phase reactions (SN 2 and Diels-Alder), and catalytic alcohol dehydration in acidic chabazite under operando conditions. Loxodynamics provides a systematic framework for reaction discovery that addresses key limitations of conventional techniques, notably by allowing acceleration without elevated temperatures or a priori knowledge of collective variables. Predicting chemical reactions remains a challenge. Here, the authors present Loxodynamics, a machine learning method that uses statistical skewness to automatically discover reaction pathways in complex systems without prior knowledge.
Nature and pH-dependent surface chemistry of TiN in aqueous environment from ab-initio and machine learning accelerated simulations Clara Saetta, Alessandro Bonardi, Riccardo Todisco, Ilaria Barlocco, Alberto Villa, Alessandro Morittu, Giovanni Maria Piccini, Giovanni Di Liberto Applied Surface Science, 2026 The nature of surfaces in aqueous environment has crucial implications in a broad series of important processes in catalysis and materials chemistry. Titanium Nitride (TiN) is a widely applied system. The atomistic nature of its interface with water and its pH-dependent surface chemistry are rather unexplored. In this work, we used density functional theory calculations in conjunction with ab initio and machine learning molecular dynamics to investigate the nature of TiN in aqueous environment. We focused on the stable (1 0 0) TiN surface. Then, we adopted the grand canonical formulation of species in solution to study the acid-base equilibrium constants on the surface and we calculated the pH at the point of zero charge (pHPZC), close to 3. We compared the predicted pHPZC with experimental measurements on commercial TiN. We also predicted the dissociation free energy of water at 298 K which is ∼0.5 eV, comparable to other materials such as TiO2. The results of this study provide an atomistic description of the nature of TiN/H2O interface. They provide some information on relevant aspects for materials chemistry and catalysis applications of TiN.
Boosting power output of microbial biofilm-based hydrovoltaic generator via surface polymerization Zhi-Wu Yan, Ting-Ting Chen, Jiajia Huang, Feng-Ying Cai, Dong Fu, Qiu-Xiang He, Han-Hui You, Guoping Ren, Qichang Hu, Christopher Rensing, GiovanniMaria Piccini, Jian Lü, Shungui Zhou Cell Reports Physical Science, 2026 Microbial biofilm-based hydrovoltaic electricity generators (BioHEGs) exemplify low-cost and facile manufacturing platforms for hydrovoltaic energy, albeit with relatively low power output that is unsatisfactory for practical applications. Herein, in situ surface polymerization of polyaniline (PAni) on Shewanella oneidensis ( S. o ) is verified to boost the hydrovoltaic performance of the biohybrid system. Notably, the S. o @PAni BioHEG unit achieves an ultra-high stable power density of ca. 168.6 mW·m −2 , which outperforms all BioHEGs hitherto documented by an order of magnitude. Specifically, the output voltage and current density of S. o @PAni BioHEG are significantly enhanced due to the formation of Schottky junctions at the interface between the microbial biofilm and electrode. Moreover, the synergistic effect of extracellular polymeric substances and PAni induces accelerated electron transfer, thereby lowering the electrical resistance in the system. This work unambiguously provides a reliable strategy for advancing the performance of BioHEGs toward more comprehensive and practical scenarios.
Protonation dynamics of confined ethanol–water mixtures in H-ZSM-5 from machine learning-driven metadynamics Princy Jarngal, Benjamin A. Jackson, Simuck F. Yuk, Difan Zhang, Mal-Soon Lee, Maria Cristina Menziani, Vassiliki-Alexandra Glezakou, Roger Rousseau, GiovanniMaria Piccini Journal of Catalysis, 2026 Zeolites are indispensable heterogeneous catalysts in industrial chemical processes, valued for their strong Brønsted acidity, well-defined microporous frameworks, and tunable pore structures. Their catalytic activity arises primarily from Brønsted acid sites (BAS), typically present as bridging hydroxyl groups (Si–OH–Al). Under aqueous reaction conditions, these protons interact dynamically with water and alcohol molecules, leading to complex solvation and protonation behavior within confined pores. In this study, we investigate the protonation equilibrium occurring between ethanol and water at the BAS of acidic zeolites under varying hydration levels, i.e., C 2 H 5 OH–(H 2 O) n , n = 1–4. Local structure was analyzed through an adaptive-learning global optimization algorithm, while enhanced sampling molecular dynamics simulations with Well-Tempered Metadynamics (WTMetaD) and machine learning interatomic potentials (MLPs) provide free-energy surfaces (FES) at variable hydration levels. The results reveal a strong dependence of proton localization on the degree of hydration. In presence of just 1 water molecule, the proton resides predominantly on ethanol; with 2 water molecules, it shifts toward water, and starting at 3, it becomes delocalized over the water cluster. These findings underscore the critical role of solvation in modulating acid site behavior and suggest that a minimum of three water molecules is necessary to fully stabilize the proton on water within the zeolite framework. This solvation threshold has significant implications for catalytic processes, particularly in biomass conversion reactions where alcohol protonation is a key step in dehydration mechanisms.
Designing Light-Sensitive Organic Semiconductors with Azobenzenes for Photoelectrochemical Transistors as Neuromorphic Platforms Isabela Berndt Paro, Martina Gini, Francesca D’ Elia, Arianna Massaro, Federica Corrado, Daniela Rana, Ana Varela, Giulia Elli, Matthias Baumann, GiovanniMaria Piccini, Luisa Petti, Daniele Leonori, Ana Belen Muñoz‐García, Michele Pavone, Andreas Offenhäusser, Valeria Criscuolo, Francesca Santoro Advanced Science, 2025 Organic neuromorphic electronics aim to emulate the adaptive behavior of biological synapses using soft, biocompatible materials capable of analog and stimulus‐responsive modulation. While azobenzene‐based semiconductors provide reversible light‐induced switching, their application in mixed ionic‐electronic conductors for neuromorphic systems remains largely unexplored. In this study, photoresponsive organic photoelectrochemical transistors (OPECTs) are engineered by functionalizing PEDOT:PSS with azobenzene derivatives bearing nitro or fluorine substituents. These modifications alter the electronic structure and surface properties of the gate, enabling systematic tuning of interfacial capacitance, a critical parameter governing photogating and neuromorphic response. Optical and electrochemical measurements, supported by DFT calculations reveal that substituent‐dependent modulation of bulk and interfacial capacitance directly impacts gating efficiency. Devices exhibit reversible, analog conductance changes under optical and electrical co‐stimulation, emulating both short‐ and long‐term synaptic plasticity. These results establish a structure–capacitance–function relationship and provide a chemically tunable platform for the development of light‐responsive neuromorphic interfaces in adaptive bioelectronics.
Molecular-Level Mechanistic Insights into PETase-Catalyzed Plastics Hydrolysis from Accurate QM/MM Free Energy Calculations Alessandro Berselli, Maria Cristina Menziani, GiovanniMaria Piccini, Francesco Muniz-Miranda ACS Catalysis, 2025 High Resolution Image Download MS PowerPoint Slide The enzyme PETase is capable of depolymerizing plastics such as polyethylene terephthalate (PET) at moderate temperatures, and demonstrated even higher activity toward polyethylene-2,5-furan dicarboxylate (PEF), opening promising routes for the efficient upcycling of plastic wastes. To fully exploit the potential of these biocatalytic systems, an understanding of the mechanism of their activity at the atomistic level is pivotal. To this end, this study investigates two fundamental stages of the catalytic cycle of PET and PEF hydrolysis by PETase─acylation and deacylation─using hybrid QM/MM enhanced sampling molecular dynamics simulations to capture all relevant dynamic effects. Well-tempered metadynamics simulations at the DFTB3 level are performed along collective variables optimized via linear discriminant analysis, a supervised learning-assisted approach that accounts for the contributions of each potentially relevant degree of freedom. The free energy (FE) profiles indicate that the acylation stage is the rate-limiting step for both PET and PEF degradation, with barriers ≈ 8 kcal/mol and ≈ 4 kcal/mol higher than those obtained for the deacylation step, respectively. Remarkably, substantial mechanistic differences are found. While PET acylation occurs in a concerted manner, with a single energy barrier of ≈ 21 kcal/mol, PEF acylation follows a two-step mechanism where after the first barrier, ≈ 10 kcal/mol high, a metastable intermediate state is formed, which then evolves toward the product once a second barrier of ≈ 2 kcal/mol is overcome. This mechanistic description is consistent with the FE profiles obtained at higher levels of theory (PBE, B3LYP, RI-MP2) via FE perturbation, thus validating the key insights elucidated by metadynamics simulations. Finally, both global and local reactivity descriptors derived from conceptual density functional theory suggest that PEF is more electrophilic and susceptible to nucleophilic attack than PET. The results obtained by means of the robust computational protocol adopted here offer thermodynamic and mechanistic insights into PET and PEF hydrolysis by PETase at the molecular level, corroborating the experimentally observed enhanced activity of this enzyme toward PEF. The distinctive hallmarks of PETase depolymerization uncovered in this work provide valuable foundations for enzyme engineering efforts aimed at developing universal biocatalysts for semiaromatic plastic recycling, ultimately paving the way for efficient application in industrial settings.
Tetrafluororesorcin[4]arene Hexameric Capsule Enables the Expansion of the Reactivity Space in Supramolecular Catalysis Tian-Ren Li, Chintu Das, GiovanniMaria Piccini, Konrad Tiefenbacher Journal of the American Chemical Society, 2025 This study presents the development and catalytic applications of the tetrafluororesorcin[4]arene hexameric capsule (capsule II) as a novel supramolecular catalyst. It demonstrates unprecedented catalytic activity, enabling the β-selective glycosylation of glycals to 2-deoxy glycosides─a transformation that has not been achieved before in molecular and supramolecular catalysis. Mechanistic investigations, including experimental and computational studies, revealed that the high β-selectivity arises from a proton wire mechanism along the capsule's surface, coupling glycal protonation with nucleophile deprotonation. Control experiments confirmed the unique reactivity of capsule II compared to its nonfluorinated predecessor, capsule I, showcasing its potential to expand the boundaries of supramolecular catalysis.
Unusual Reaction of Isocyanides with Aromatic Aldehydes Catalyzed by a Supramolecular Capsule Luca Fiorini, Jesper Köster, GiovanniMaria Piccini, Bernd Goldfuss, Alessandro Prescimone, Fabrizio Fabris, Konrad Tiefenbacher, Alessandro Scarso Chemistry A European Journal, 2025 The supramolecular resorcinarene hexameric capsule efficiently promotes the unprecedented reaction between isocyanides and electron‐deficient aromatic aldehydes leading to the formation of imines and carbon monoxide. The mechanism of the reaction was investigated via isotope labelling, kinetic analysis of the reaction, computational studies and the independent synthesis of a proposed intermediate. Control experiments indicate that the formation of the key aziridinone intermediate is limited to the cavity of the capsule.
FESTA: A Polygon-Based Approach for Extracting Relevant Structures from Free Energy Surfaces Obtained in Molecular Simulations Valentin Istomin, GiovanniMaria Piccini Journal of Chemical Information and Modeling, 2025 An easy-to-use script named FESTA (Free Energy Surface Trajectory Analysis) is provided to streamline the extraction of equilibrium structures from free energy maps obtained with enhanced sampling simulation techniques and their associated trajectories. This approach efficiently identifies relevant structures by automatically selecting minima on the free energy surface using a connected-component labeling algorithm and extracts them utilizing a Shapely-polygon-based trajectory analysis process. The script is general and portable; it incorporates an automatic periodicity detection system; and multiprocessing is utilized to leverage all available computational resources for enhanced efficiency. The effectiveness of the proposed polygon-based approach is demonstrated through comparison with a naïve and largely inefficient loop-based script and its application across three distinct systems for benchmarking purposes.
Window[1]resorcin[3]arenes: A Novel Macrocycle Able to Self-Assemble to a Catalytically Active Hexameric Cage Tian-Ren Li, Chintu Das, Ivan Cornu, Alessandro Prescimone, GiovanniMaria Piccini, Konrad Tiefenbacher Jacs Au, 2024 The hexameric resorcin[4]arene capsule has been utilized as one of the most versatile supramolecular capsule catalysts. Enlarging its size would enable expansion of the substrate size scope. However, no larger catalytically active versions have been reported. Herein, we introduce a novel class of macrocycles, named window[1]resorcin[3]arene (wRS), that assemble to a cage-like hexameric host. The new host was studied by NMR, encapsulation experiments, and molecular dynamics simulations. The cage is able to bind tetraalkylammonium ions that are too large for encapsulation inside the hexameric resorcin[4]arene capsule. Most importantly, it retained its catalytic activity, and the accelerated conversion of a large substrate that does not fit the closed hexameric resorcin[4]arene capsule was observed. Thus, it will help to expand the limited substrate size scope of the closed hexameric resorcin[4]arene capsule.
Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes Mirko Paulikat, Daniele Vitone, Florian K. Schackert, Nils Schuth, Alessandra Barbanente, GiovanniMaria Piccini, Emiliano Ippoliti, Giulia Rossetti, Adam H. Clark, Maarten Nachtegaal, Michael Haumann, Holger Dau, Paolo Carloni, Silvano Geremia, Rita De Zorzi, Liliana Quintanar, Fabio Arnesano Journal of Chemical Information and Modeling, 2023
Assessing entropy for catalytic processes at complex reactive interfaces Loukas Kollias, Gregory Collinge, Difan Zhang, Sarah I. Allec, Pradeep Kumar Gurunathan, GiovanniMaria Piccini, Simuck F. Yuk, Manh-Thuong Nguyen, Mal-Soon Lee, Vassiliki-Alexandra Glezakou, Roger Rousseau Annual Reports in Computational Chemistry, 2022
Confinement effects and acid strength in zeolites Emanuele Grifoni, GiovanniMaria Piccini, Johannes A. Lercher, Vassiliki-Alexandra Glezakou, Roger Rousseau, Michele Parrinello Nature Communications, 2021
Microscopic description of acid–base equilibrium Emanuele Grifoni, GiovanniMaria Piccini, Michele Parrinello Proceedings of the National Academy of Sciences of the United States of America, 2019
Boosting power output of microbial biofilm-based hydrovoltaic generator via surface polymerization ZW Yan, TT Chen, J Huang, FY Cai, D Fu, QX He, HH You, G Ren, Q Hu, ... Cell Reports Physical Science 7 (5) , 2026 2026
Nature and pH-dependent surface chemistry of TiN in aqueous environment from ab-initio and machine learning accelerated simulations C Saetta, A Bonardi, R Todisco, I Barlocco, A Villa, A Morittu, GM Piccini, ... Applied Surface Science, 167089 , 2026 2026
The Elusive Nature of Aromatic Carbocation Intermediates in Confined Catalytic Environments GM Piccini, C Das, P Jarngal, F Berger, A Khetan 2026
Exploring chemistry and catalysis by biasing skewed distributions via deep learning Z Zhang, GM Piccini Nature Communications , 2026 2026 Citations: 1
To Be or Not to Be: The Elusive Nature of Wheland-type Intermediates in Zeolite-Catalyzed Aromatic Alkylation Revealed by CCSD (T)-quality Metadynamics C Das, P Jarngal, F Berger, GM Piccini ChemRxiv 2026 (0113) , 2026 2026
Protonation dynamics of confined ethanol–water mixtures in H-ZSM-5 from machine learning-driven metadynamics P Jarngal, BA Jackson, SF Yuk, D Zhang, MS Lee, MC Menziani, ... Journal of Catalysis, 116658 , 2025 2025
Designing Light‐Sensitive Organic Semiconductors with Azobenzenes for Photoelectrochemical Transistors as Neuromorphic Platforms I Berndt Paro, M Gini, F D’Elia, A Massaro, F Corrado, D Rana, A Varela, ... Advanced Science 12 (39), e09125 , 2025 2025 Citations: 4
Molecular-level mechanistic insights into PETase-catalyzed plastics hydrolysis from accurate QM/MM free energy calculations A Berselli, MC Menziani, GM Piccini, F Muniz-Miranda ACS Catalysis 15 (12), 10702-10721 , 2025 2025 Citations: 9
Unusual Reaction of Isocyanides with Aromatic Aldehydes Catalyzed by a Supramolecular Capsule L Fiorini, J Köster, GM Piccini, B Goldfuss, A Prescimone, F Fabris, ... Chemistry–A European Journal 31 (14), e202404061 , 2025 2025
Tetrafluororesorcin [4] arene hexameric capsule enables the expansion of the reactivity space in supramolecular catalysis TR Li, C Das, GM Piccini, K Tiefenbacher Journal of the American Chemical Society 147 (13), 11108-11116 , 2025 2025 Citations: 8
FESTA: A Polygon-Based Approach for Extracting Relevant Structures from Free Energy Surfaces Obtained in Molecular Simulations V Istomin, GM Piccini Journal of Chemical Information and Modeling 65 (1), 1-6 , 2024 2024 Citations: 4
Window [1] resorcin [3] arenes: A Novel Macrocycle Able to Self-Assemble to a Catalytically Active Hexameric Cage TR Li, C Das, I Cornu, A Prescimone, GM Piccini, K Tiefenbacher JACS Au 4 (5), 1901-1910 , 2024 2024 Citations: 7
Lithium-ion hopping weakens thermal stability of LiPF6 carbonate electrolytes KS Han, MS Lee, N Kim, D Choi, S Chae, J Ryu, GM Piccini, R Rousseau, ... Cell Reports Physical Science 5 (1) , 2024 2024 Citations: 28
Atomistic insights into hydrogen-bonded supramolecular capsule self-assembly dynamics R Capelli, GM Piccini The Journal of Physical Chemistry C 128 (1), 635-641 , 2023 2023 Citations: 14
Physical chemistry of chloroquine permeation through the cell membrane with atomistic detail M Paulikat, GM Piccini, E Ippoliti, G Rossetti, F Arnesano, P Carloni Journal of Chemical Information and Modeling 63 (22), 7124-7132 , 2023 2023 Citations: 7
Physical Chemistry of Drug Permeation through the Cell Membrane with Atomistic Detail M Paulikat, GM Piccini, E Ippoliti, G Rossetti, F Arnesano, P Carloni bioRxiv, 2023.07. 24.550356 , 2023 2023
Supramolecular Capsule-Catalyzed Highly β-Selective Furanosylation Independent of the S N 1/S N 2 Reaction Pathway TR Li, GM Piccini, K Tiefenbacher Journal of the American Chemical Society 145 (7), 4294-4303 , 2023 2023 Citations: 31
Molecular dynamics and structural studies of zinc chloroquine complexes M Paulikat, D Vitone, FK Schackert, N Schuth, A Barbanente, GM Piccini, ... Journal of Chemical Information and Modeling 63 (1), 161-172 , 2022 2022 Citations: 12
Mimicry of the proton wire mechanism of enzymes inside a supramolecular capsule enables beta-selective O-glycosylations (Jul, 10.1038/s41557-022-00981-6, 2022) TR Li, F Huck, GM Piccini, K Tiefenbacher NATURE CHEMISTRY 14 (9), 1086-1086 , 2022 2022
Mimicry of the proton wire mechanism of enzymes inside a supramolecular capsule enables β-selective O -glycosylations TR Li, F Huck, GM Piccini, K Tiefenbacher Nature Chemistry 14 (9), 985-994 , 2022 2022 Citations: 77
MOST CITED SCHOLAR PUBLICATIONS
Promoting transparency and reproducibility in enhanced molecular simulations Nature methods 16 (8), 670-673 , 2019 2019 Citations: 1089
Deep learning the slow modes for rare events sampling L Bonati, GM Piccini, M Parrinello Proceedings of the National Academy of Sciences 118 (44), e2113533118 , 2021 2021 Citations: 272
Collective variables from local fluctuations D Mendels, GM Piccini, M Parrinello The journal of physical chemistry letters 9 (11), 2776-2781 , 2018 2018 Citations: 205
Confinement effects and acid strength in zeolites E Grifoni, GM Piccini, JA Lercher, VA Glezakou, R Rousseau, M Parrinello Nature communications 12 (1), 2630 , 2021 2021 Citations: 193
Accurate adsorption thermodynamics of small alkanes in zeolites. Ab initio theory and experiment for H-chabazite GM Piccini, M Alessio, J Sauer, Y Zhi, Y Liu, R Kolvenbach, A Jentys, ... The Journal of Physical Chemistry C 119 (11), 6128-6137 , 2015 2015 Citations: 176
Effect of anharmonicity on adsorption thermodynamics GM Piccini, J Sauer Journal of chemical theory and computation 10 (6), 2479-2487 , 2014 2014 Citations: 151
Ab initio calculation of rate constants for molecule–surface reactions with chemical accuracy GM Piccini, M Alessio, J Sauer Angewandte Chemie International Edition 55 (17), 5235-5237 , 2016 2016 Citations: 138
Ab initio molecular dynamics with enhanced sampling in heterogeneous catalysis GM Piccini, MS Lee, SF Yuk, D Zhang, G Collinge, L Kollias, MT Nguyen, ... Catalysis Science & Technology 12 (1), 12-37 , 2022 2022 Citations: 104
Ab initio prediction of adsorption isotherms for small molecules in metal–organic frameworks A Kundu, GM Piccini, K Sillar, J Sauer Journal of the American Chemical Society 138 (42), 14047-14056 , 2016 2016 Citations: 87
Requirements for terpene cyclizations inside the supramolecular resorcinarene capsule: bound water and its protonation determine the catalytic activity S Merget, L Catti, GM Piccini, K Tiefenbacher Journal of the American Chemical Society 142 (9), 4400-4410 , 2020 2020 Citations: 82
Metadynamics with discriminants: A tool for understanding chemistry GM Piccini, D Mendels, M Parrinello Journal of chemical theory and computation 14 (10), 5040-5044 , 2018 2018 Citations: 82
Gold nanowires: a time-dependent density functional assessment of plasmonic behavior GM Piccini, RWA Havenith, R Broer, M Stener The Journal of Physical Chemistry C 117 (33), 17196-17204 , 2013 2013 Citations: 80
Mimicry of the proton wire mechanism of enzymes inside a supramolecular capsule enables β-selective O -glycosylations TR Li, F Huck, GM Piccini, K Tiefenbacher Nature Chemistry 14 (9), 985-994 , 2022 2022 Citations: 77
Chasing the full free energy landscape of neuroreceptor/ligand unbinding by metadynamics simulations R Capelli, A Bochicchio, GM Piccini, R Casasnovas, P Carloni, ... Journal of chemical theory and computation 15 (5), 3354-3361 , 2019 2019 Citations: 67
Folding a small protein using harmonic linear discriminant analysis D Mendels, G Piccini, ZF Brotzakis, YI Yang, M Parrinello The Journal of chemical physics 149 (19) , 2018 2018 Citations: 67
Quantum chemical free energies: Structure optimization and vibrational frequencies in normal modes GM Piccini, J Sauer Journal of chemical theory and computation 9 (11), 5038-5045 , 2013 2013 Citations: 67
Microscopic description of acid–base equilibrium E Grifoni, GM Piccini, M Parrinello Proceedings of the National Academy of Sciences 116 (10), 4054-4057 , 2019 2019 Citations: 63
Improving collective variables: The case of crystallization YY Zhang, H Niu, GM Piccini, D Mendels, M Parrinello The Journal of chemical physics 150 (9) , 2019 2019 Citations: 58
Including dispersion in density functional theory for adsorption on flat oxide surfaces, in metal–organic frameworks and in acidic zeolites FR Rehak, GM Piccini, M Alessio, J Sauer Physical Chemistry Chemical Physics 22 (14), 7577-7585 , 2020 2020 Citations: 56
Ab initio study of methanol and ethanol adsorption on Brønsted sites in zeolite H-MFI GM Piccini, M Alessio, J Sauer Physical Chemistry Chemical Physics 20 (30), 19964-19970 , 2018 2018 Citations: 53
