Structural Characterization and AI-Enhanced Modeling of a Broadly Neutralizing Camelid Antibody Against SARS-CoV-2 Variants Katja Hanack, Urszula Orzeł, Anja Schlör, Sourabh Mehta, Anandi Krishnan, et al. Advanced Therapeutics, 2026 The Omicron variants of SARS‐CoV‐2 are characterized by their high transmissibility and immune evasion. Existing treatments using neutralizing antibodies have shown different effectiveness due to variants with mutations occurring mainly in the RBD and NTD regions. In this study, the functional neutralizing ability of a camelid full‐length antibody (hcAb‐B10) and its corresponding VHH fragment (VHH‐B10) is investigated. Experimental binding studies demonstrated clear recognition and neutralization of Wild‐type (WT) and Omicron variants, but not Delta. Epitope mapping, peptide fragment inhibition, and neutralization studies using pseudovirus expressing respective SARS‐CoV‐2 Spike variants, along with in silico molecular docking studies and AI‐directed structural design, reveal that the B10 antibody interacts effectively with the Spike trimer in a closed position of both WT and Omicron, by targeting the RBD region. This newly generated B10 antibody shows a wide coverage, including the currently dominant Omicron variants, and demonstrates its potential to efficiently neutralize SARS‐CoV‐2.
Conformational Changes and Unfolding of β-Amyloid Substrates in the Active Site of γ-Secretase Jakub Jakowiecki, Urszula Orzeł, Przemysław Miszta, Krzysztof Młynarczyk, Sławomir Filipek International Journal of Molecular Sciences, 2024 Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aβ40 and Aβ42, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aβ40, indicating why trimming of this substrate is so infrequent.
GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the γ-secretase complex Urszula Orzeł, Paweł Pasznik, Przemysław Miszta, Marcin Lorkowski, Szymon Niewieczerzał, et al. Nucleic Acids Research, 2023 Despite recent advances in research, the mechanism of Alzheimer's disease is not fully understood yet. Understanding the process of cleavage and then trimming of peptide substrates, can help selectively block γ-secretase (GS) to stop overproduction of the amyloidogenic products. Our GS-SMD server (https://gs-smd.biomodellab.eu/) allows cleaving and unfolding of all currently known GS substrates (more than 170 peptide substrates). The substrate structure is obtained by threading of the substrate sequence into the known structure of GS complex. The simulations are performed in an implicit water-membrane environment so they are performed rather quickly, 2–6 h per job, depending on the mode of calculations (part of GS complex or the whole structure). It is also possible to introduce mutations to the substrate and GS and pull any part of the substrate in any direction using the steered molecular dynamics (SMD) simulations with constant velocity. The obtained trajectories are visualized and analyzed in the interactive way. One can also compare multiple simulations using the interaction frequency analysis. GS-SMD server can be useful for revealing mechanisms of substrate unfolding and role of mutations in this process.
Cross-variant immune shield: computational multiepitope vaccine design against B. 617.2 to Omicron sub-lineages in SARS-CoV-2 JM Thakor, UV Panchal, D Patel, S Filipek, U Orzeł, R Paulmurugan, ... Journal of Biomolecular Structure and Dynamics 44 (2), 983-1002 , 2026 2026.0 Citations: 1
Cover Feature: Structural Characterization and AI‐Enhanced Modeling of a Broadly Neutralizing Camelid Antibody Against SARS‐CoV‐2 Variants (Adv. Therap. 1/2026) K Hanack, U Orzeł, A Schlör, S Mehta, A Krishnan, S Filipek, R Patel, ... Advanced Therapeutics 9 (1), e70113 , 2026 2026.0
Structural Characterization and AI‐Enhanced Modeling of a Broadly Neutralizing Camelid Antibody Against SARS‐CoV‐2 Variants K Hanack, U Orzeł, A Schlör, S Mehta, A Krishnan, S Filipek, R Patel, ... Advanced Therapeutics 9 (1), e00244 , 2026 2026.0
Artificial intelligence in rare diseases: toward clinical impact AMB Amorim, U Orzeł, AB Caniceiro, N Rosário-Ferreira, IS Moreira Trends in Pharmacological Sciences , 2025 2025.0 Citations: 5
GPCR oligomerization across classes: A2AR-mediated regulation of mGlu5R activation U Orzeł, CAV Barreto, S Filipek, IS Moreira International Journal of Biological Macromolecules 299, 139880 , 2025 2025.0 Citations: 2
Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways D Aranda-García, TM Stepniewski, M Torrens-Fontanals, A García-Recio, ... Nature communications 16 (1), 2020 , 2025 2025.0 Citations: 52
Leveraging artificial intelligence in GPCR activation studies: computational prediction methods as key drivers of knowledge AB Caniceiro, U Orzeł, N Rosário-Ferreira, S Filipek, IS Moreira Protein Supersecondary Structures: Methods and Protocols, 183-220 , 2024 2024.0 Citations: 9
Conformational changes and unfolding of β-amyloid substrates in the active site of γ-secretase J Jakowiecki, U Orzeł, P Miszta, K Młynarczyk, S Filipek International Journal of Molecular Sciences 25 (5), 2564 , 2024 2024.0 Citations: 2
Investigation of peptides for molecular recognition of C-reactive protein–theoretical and experimental studies K Szot-Karpinska, P Kudła, U Orzeł, M Narajczyk, M Jönsson-Niedziółka, ... Analytical Chemistry 95 (38), 14475-14483 , 2023 2023.0 Citations: 15
GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the γ-secretase complex U Orzeł, P Pasznik, P Miszta, M Lorkowski, S Niewieczerzał, J Jakowiecki, ... Nucleic Acids Research 51 (W1), W251-W262 , 2023 2023.0 Citations: 3
Specificities of Protein Homology Modeling for Allosteric Drug Design J Jakowiecki, U Orzeł, A Gliździnska, M Możajew, S Filipek Homology Modeling: Methods and Protocols, 339-348 , 2023 2023.0
The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex U Orzeł, J Jakowiecki, K Młynarczyk, S Filipek Biomolecules 11 (7), 935 , 2021 2021.0 Citations: 10
Allosteric modulation of the CB1 cannabinoid receptor by cannabidiol—A molecular modeling study of the N-terminal domain and the allosteric-orthosteric coupling J Jakowiecki, R Abel, U Orzeł, P Pasznik, R Preissner, S Filipek Molecules 26 (9), 2456 , 2021 2021.0 Citations: 52
The hydrophobic ligands entry and exit from the GPCR binding site-SMD and SUMD simulations J Jakowiecki, U Orzeł, S Chawananon, P Miszta, S Filipek Molecules 25 (8), 1930 , 2020 2020.0 Citations: 17
Computational methods to study the structure and dynamics of biomolecules and biomolecular processes D Latek, B Trzaskowski, S Niewieczerzał, P Miszta, K Młynarczyk, ... Springer , 2019 2019.0 Citations: 10
Modeling of Membrane Proteins W Puławski, S Yuan, A Sztyler, U Orzeł Computational Methods to Study the Structure and Dynamics of Biomolecules … , 2018 2018.0
Modeling of membrane proteins D Latek, B Trzaskowski, S Niewieczerzał, P Miszta, K Młynarczyk, ... Computational Methods to Study the Structure and Dynamics of Biomolecules … , 2018 2018.0 Citations: 10
OC12–Urszula Orzeł U Orzeł, B Bueshbell, C Baretto, S Flipek, IS Moreira 3D-BIOINFO-PT, 29 , 0
MOST CITED SCHOLAR PUBLICATIONS
Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways D Aranda-García, TM Stepniewski, M Torrens-Fontanals, A García-Recio, ... Nature communications 16 (1), 2020 , 2025 2025.0 Citations: 52
Allosteric modulation of the CB1 cannabinoid receptor by cannabidiol—A molecular modeling study of the N-terminal domain and the allosteric-orthosteric coupling J Jakowiecki, R Abel, U Orzeł, P Pasznik, R Preissner, S Filipek Molecules 26 (9), 2456 , 2021 2021.0 Citations: 52
The hydrophobic ligands entry and exit from the GPCR binding site-SMD and SUMD simulations J Jakowiecki, U Orzeł, S Chawananon, P Miszta, S Filipek Molecules 25 (8), 1930 , 2020 2020.0 Citations: 17
Investigation of peptides for molecular recognition of C-reactive protein–theoretical and experimental studies K Szot-Karpinska, P Kudła, U Orzeł, M Narajczyk, M Jönsson-Niedziółka, ... Analytical Chemistry 95 (38), 14475-14483 , 2023 2023.0 Citations: 15
The Role of Cholesterol in Amyloidogenic Substrate Binding to the γ-Secretase Complex U Orzeł, J Jakowiecki, K Młynarczyk, S Filipek Biomolecules 11 (7), 935 , 2021 2021.0 Citations: 10
Computational methods to study the structure and dynamics of biomolecules and biomolecular processes D Latek, B Trzaskowski, S Niewieczerzał, P Miszta, K Młynarczyk, ... Springer , 2019 2019.0 Citations: 10
Modeling of membrane proteins D Latek, B Trzaskowski, S Niewieczerzał, P Miszta, K Młynarczyk, ... Computational Methods to Study the Structure and Dynamics of Biomolecules … , 2018 2018.0 Citations: 10
Leveraging artificial intelligence in GPCR activation studies: computational prediction methods as key drivers of knowledge AB Caniceiro, U Orzeł, N Rosário-Ferreira, S Filipek, IS Moreira Protein Supersecondary Structures: Methods and Protocols, 183-220 , 2024 2024.0 Citations: 9
Artificial intelligence in rare diseases: toward clinical impact AMB Amorim, U Orzeł, AB Caniceiro, N Rosário-Ferreira, IS Moreira Trends in Pharmacological Sciences , 2025 2025.0 Citations: 5
GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the γ-secretase complex U Orzeł, P Pasznik, P Miszta, M Lorkowski, S Niewieczerzał, J Jakowiecki, ... Nucleic Acids Research 51 (W1), W251-W262 , 2023 2023.0 Citations: 3
GPCR oligomerization across classes: A2AR-mediated regulation of mGlu5R activation U Orzeł, CAV Barreto, S Filipek, IS Moreira International Journal of Biological Macromolecules 299, 139880 , 2025 2025.0 Citations: 2
Conformational changes and unfolding of β-amyloid substrates in the active site of γ-secretase J Jakowiecki, U Orzeł, P Miszta, K Młynarczyk, S Filipek International Journal of Molecular Sciences 25 (5), 2564 , 2024 2024.0 Citations: 2
Cross-variant immune shield: computational multiepitope vaccine design against B. 617.2 to Omicron sub-lineages in SARS-CoV-2 JM Thakor, UV Panchal, D Patel, S Filipek, U Orzeł, R Paulmurugan, ... Journal of Biomolecular Structure and Dynamics 44 (2), 983-1002 , 2026 2026.0 Citations: 1
Cover Feature: Structural Characterization and AI‐Enhanced Modeling of a Broadly Neutralizing Camelid Antibody Against SARS‐CoV‐2 Variants (Adv. Therap. 1/2026) K Hanack, U Orzeł, A Schlör, S Mehta, A Krishnan, S Filipek, R Patel, ... Advanced Therapeutics 9 (1), e70113 , 2026 2026.0
Structural Characterization and AI‐Enhanced Modeling of a Broadly Neutralizing Camelid Antibody Against SARS‐CoV‐2 Variants K Hanack, U Orzeł, A Schlör, S Mehta, A Krishnan, S Filipek, R Patel, ... Advanced Therapeutics 9 (1), e00244 , 2026 2026.0
Specificities of Protein Homology Modeling for Allosteric Drug Design J Jakowiecki, U Orzeł, A Gliździnska, M Możajew, S Filipek Homology Modeling: Methods and Protocols, 339-348 , 2023 2023.0
Modeling of Membrane Proteins W Puławski, S Yuan, A Sztyler, U Orzeł Computational Methods to Study the Structure and Dynamics of Biomolecules … , 2018 2018.0
OC12–Urszula Orzeł U Orzeł, B Bueshbell, C Baretto, S Flipek, IS Moreira 3D-BIOINFO-PT, 29 , 0
