Currently, monoclonal antibodies (mAbs) are the most used biopharmaceuticals for human therapy. One of the key aspects in their development is the control of effector functions mediated by the interaction between fragment crystallizable (Fc) and Fcγ receptors, which is a secondary mechanism of the action of biotherapeutics. N-glycosylation at the Fc portion can regulate these mechanisms, and much experimental evidence suggests that modifications of glycosidic chains can affect antibody binding to FcγRIIIa, consequently impacting the immune response. In this work, we try to elucidate via in silico procedures the structural role exhibited by glycans, particularly fucose, in mAb conformational freedom that can potentially affect the receptor recognition. By using adalimumab, a marketed IgG1, as a general template, after rebuilding its three-dimensional (3D) structure through homology modeling approaches, we carried out molecular dynamics simulations of three differently glycosylated species: aglycosylated, afucosylated, and fucosylated antibody. Trajectory analysis showed different dynamical behaviors and pointed out that sugars can influence the overall 3D structure of the antibody. As a result, we propose a putative structural mechanism by which the presence of fucose introduces conformational constraints in the whole antibody and not only in the Fc domain, preventing a conformation suitable for the interaction with the receptor. As secondary evidence, we observed a high flexibility of the antibodies that is translated into an asymmetric behavior of Fab portions shown by all the simulated biopolymers, making the dynamical asymmetry a new, to our knowledge, molecular aspect that may be further investigated. In conclusion, these findings can help understand the contribution of sugars on the structural architecture of mAbs, paving the way to novel strategies of pharmaceutical development.
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http://dx.doi.org/10.1016/j.bpj.2021.10.026 | DOI Listing |
J Biomol Struct Dyn
January 2025
University of Health Sciences, Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Vietnam.
The COVID-19 pandemic posed a threat to global society. Delta and Omicron are concerning variants due to the risk of increasing human-to-human transmissibility and immune evasion. This study aims to evaluate the binding ability of these variants toward the angiotensin-converting enzyme 2 receptor and antibodies using a computational approach.
View Article and Find Full Text PDFJ Biomol Struct Dyn
January 2025
College of Applied Medical Sciences, lmam Abdulrahman Bin Faisal University (lAU), Dammam, Saudi Arabia.
The present study explores the conformational dynamics of the membrane protein of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) within the Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC) complex using an all-atomistic molecular dynamics simulation approach. Significant structural changes were observed in the N-terminal, C-terminal, transmembrane, and beta-sheet sandwich domains of the MERS-CoV membrane protein. This study also highlights the structural similarities between the MERS-CoV and the SARS-CoV-2 membrane proteins, particularly in how both exhibit a distinct kink in the transmembrane helix caused by aromatic residue-lipid interactions.
View Article and Find Full Text PDFSci Rep
January 2025
College of Mechanical Engineering, Zhejiang University of Technology, No.18, Chaowang Road, Hangzhou, 310014, Zhejiang Province, China.
To observe the chemical mechanical polishing (CMP) process at the atomic scale, reactive force field molecular dynamics (ReaxFF-MD) was employed to simulate the polishing of 6 H-SiC under three conditions: dry, pure water, and HO solution. This study examined the reactants on the surface of 6 H-SiC during the reaction in the HO solution, along with the dissociation and adsorption processes of HO and water molecules. The mechanisms for atom removal during the CMP process were elucidated.
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January 2025
School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Vibrio vulnificus is a significant zoonotic pathogen that causes severe vibriosis in humans and fish. The lack of a national annual surveillance program in China has hindered understanding of its epidemiological characteristics and genetic diversity. This study characterized 150 V.
View Article and Find Full Text PDFSci Rep
January 2025
Bioinformatics Centre, Savitribai Phule Pune University, Pune, Maharashtra, 411007, India.
COVID-19 has proved to be a global health crisis during the pandemic, and the emerging JN.1 variant is a potential threat. Therefore, finding alternative antivirals is of utmost priority.
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