MARIA LAURA DE SCISCIO

PhD Graduate

PhD program:: XXXVII


supervisor: Marco D'Abramo

Thesis title: Computational Methods For the Development of Biotherapeutic Products

The development process of biotherapeutic products faces remarkable challenges in identifying novel, effective and safe candidates, with chemical stability emerging as a critical obstacle that hinders the discovery process. This thesis provides a comprehensive evaluation of the thermodynamics and kinetics of two of the most common spontaneous Post-Translational Modifications (PTMs), namely asparagine deamidation and methionine oxidation, whose occurrence can compromise the efficacy and immunogenicity of the biotherapeutics under development. By employing a rigorous theoretical-computational framework, that integrates Quantum Mechanics, hybrid Quantum Mechanics/Molecular Mechanics and Molecular Dynamics approaches, we sought to decipher the molecular mechanism underlying these PTMs reactions. A bottom-up computational strategy was adopted, which comprises investigations on simple molecular models, extension to real systems and quantitative validation against tailored experiments and literature data. This strategy has yielded novel insights into the behavior of such reactions in proteins, unveiling the critical role of hydrogen peroxide diffusion in modulating methionine oxidation. Conversely, features such as amide acidity, conformational degrees of freedom, and environmental electrostatics were identified as key determinants of asparagine reactivity towards deamidation. These findings enhanced our understanding of these chemical reactions and facilitated more accurate predictions in several proteins, paving the way for future studies on a more extended scale. Moreover, this thesis demonstrates the efficacy of an integrative modelling approach to rationalize mutagenesis effects, which is essential to capture the inherent flexibility of monoclonal antibodies (mAb), the dominant class of biotherapeutics. Indeed, by coupling computational and experimental assays, we elucidated the structural-dynamics features behind the novel identified framework positions to tune mAb-antigen binding, which could provide valuable insights in the sequence optimization stage of development.

Research products

11573/1713419 - 2024 - Conformational and dynamic properties of the KH1 domain of FMRP and its fragile X syndrome linked G266E variant
Catalano, Flavia; Santorelli, Daniele; Astegno, Alessandra; Favretto, Filippo; D’Abramo, Marco; Del Giudice, Alessandra; De Sciscio, Maria Laura; Troilo, Francesca; Giardina, Giorgio; Di Matteo, Adele; Travaglini-Allocatelli, Carlo - 01a Articolo in rivista
paper: BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS (Tokyo ; Oxford ; New York ; London ; Amsterdam ; Shannon ; Paris : Elsevier) pp. 1-8 - issn: 1570-9639 - wos: WOS:001233726500001 (0) - scopus: 2-s2.0-85190942366 (0)

11573/1715634 - 2024 - Binding of steroid substrates reveals the key to the productive transition of the cytochrome P450 OleP
Costanzo, Antonella; Fata, Francesca; Freda, Ida; De Sciscio, Maria Laura; Gugole, Elena; Bulfaro, Giovanni; Di Renzo, Matteo; Barbizzi, Luca; Exertier, Cécile; Parisi, Giacomo; D’Abramo, Marco; Vallone, Beatrice; Savino, Carmelinda; Montemiglio, Linda Celeste - 01a Articolo in rivista
paper: STRUCTURE (London: Current Biology.) pp. 1465-1476 - issn: 0969-2126 - wos: WOS:001309530300001 (1) - scopus: 2-s2.0-85198611397 (1)

11573/1707635 - 2024 - Modelling the assembly and flexibility of antibody structures
Guo, Dongjun; De Sciscio, Maria Laura; Chi-Fung Ng, Joseph; Fraternali, Franca - 01g Articolo di rassegna (Review)
paper: CURRENT OPINION IN STRUCTURAL BIOLOGY (Current Biology Limited:84 Theobalds Road, London WC1X 8RR United Kingdom:011 44 20 76114202, EMAIL: info@biomednet.com, INTERNET: http://www.biomednet.com, Fax: 011 44 20 76114479) pp. 1-9 - issn: 0959-440X - wos: WOS:001142966400001 (4) - scopus: 2-s2.0-85180584780 (5)

11573/1711624 - 2024 - A finely balanced order–disorder equilibrium sculpts the folding–binding landscape of an antibiotic sequestering protein
Natarajan, Lawanya; De Sciscio, Maria Laura; Nardi, Alessandro Nicola; Sekhar, Ashok; Del Giudice, Alessandra; D'abramo, Marco; Naganathan, Athi N. - 01a Articolo in rivista
paper: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (National Academy of Sciences:2101 Constitution Avenue Northwest:Washington, DC 20418:(877)314-2253, (615)377-3322, EMAIL: subspnas@nas.edu, INTERNET: http://www.pnas.org, Fax: (615)377-0525) pp. 1-12 - issn: 0027-8424 - wos: WOS:001235811700002 (1) - scopus: 2-s2.0-85192637766 (0)

11573/1693500 - 2023 - Computational and Experimental Drug Repurposing of FDA-Approved Compounds Targeting the Cannabinoid Receptor CB1
Criscuolo, Emanuele; De Sciscio, Maria Laura; De Cristofaro, Angela; Nicoara, Catalin; Maccarrone, Mauro; Fezza, Filomena - 01a Articolo in rivista
paper: PHARMACEUTICALS (Basel: MDPI, Molecular Diversity Preservation International, 2004-) pp. 1-14 - issn: 1424-8247 - wos: WOS:001131337300001 (1) - scopus: 2-s2.0-85180720769 (1)

11573/1693390 - 2023 - Molecular Modeling of the Deamidation Reaction in Solution: A Theoretical-Computational Study
De Sciscio, Maria Laura; Nardi, Alessandro Nicola; Centola, Fabio; Rossi, Mara; Guarnera, Enrico; D'abramo, Marco - 01a Articolo in rivista
paper: THE JOURNAL OF PHYSICAL CHEMISTRY. B (Columbus, OH : American Chemical Society, 1997-) pp. 9550-9559 - issn: 1520-5207 - wos: WOS:001098413700001 (3) - scopus: 2-s2.0-85176509378 (3)

11573/1665426 - 2023 - Effect of salts on the conformational dynamics of the Cytochrome P450 OleP
De Sciscio, Maria Laura; Nardi, Alessandro Nicola; Parisi, Giacomo; Bulfaro, Giovanni; Costanzo, Antonella; Gugole, Elena; Exertier, Cécile; Freda, Ida; Savino, Carmelinda; Vallone, Beatrice; Montemiglio, Linda Celeste; D’Abramo, Marco - 01a Articolo in rivista
paper: MOLECULES (Basel: MDPI Berlin: Springer, 1996-) pp. - - issn: 1420-3049 - wos: WOS:000927697700001 (1) - scopus: 2-s2.0-85146781706 (1)

11573/1688794 - 2023 - Fatty acid amide hydrolase, anandamide, and neurological diseases
Fezza, F.; Criscuolo, E.; De Sciscio, M. L.; Maccarrone, M. - 02a Capitolo o Articolo
book: Neurobiology and Physiology of the Endocannabinoid System - (9780323908771)

11573/1664892 - 2022 - Theoretical evaluation of sulfur-based reactions as a model for biological antioxidant defense
De Sciscio, Maria Laura; D’Annibale, Valeria; D’Abramo, Marco - 01a Articolo in rivista
paper: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 1-14 - issn: 1422-0067 - wos: WOS:000896382800001 (7) - scopus: 2-s2.0-85143774799 (8)

11573/1603246 - 2021 - In silico and in vitro analysis of major cannabis-derived compounds as fatty acid amide hydrolase inhibitors
Criscuolo, E.; De Sciscio, M. L.; Fezza, F.; Maccarrone, M. - 01a Articolo in rivista
paper: MOLECULES (Basel: MDPI Berlin: Springer, 1996-) pp. 1-8 - issn: 1420-3049 - wos: WOS:000606119100001 (8) - scopus: 2-s2.0-85099116033 (9)

11573/1603248 - 2021 - Exploring the role of l10 loop in new delhi metallo-β-lactamase (Ndm-1): Kinetic and dynamic studies
Piccirilli, A.; Criscuolo, E.; Brisdelli, F.; Mercuri, P. S.; Cherubini, S.; De Sciscio, M. L.; Maccarrone, M.; Galleni, M.; Amicosante, G.; Perilli, M. - 01a Articolo in rivista
paper: MOLECULES (Basel: MDPI Berlin: Springer, 1996-) pp. 1-14 - issn: 1420-3049 - wos: WOS:000701939200001 (5) - scopus: 2-s2.0-85114912058 (5)

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