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Epidermal Growth Factor Receptor (EGFR) is a glycosylated tyrosine kinase receptor associated with several cancers. EGFR plays an important role in cancer therapy and inspired several experimental and computational (molecular dynamics simulation) studies to investigate its function and dynamics. N-glycosylation is a critical aspect of EGFR functioning that was mainly unexplained until recently due to the challenges in obtaining and analysis of the structural data involving the glycan moieties. Latest simulations of glycosylated EGFR suggest atomistic mechanisms underlying the experimentally proposed functions of N-glycans in: EGFR increased ligand binding, reduced flexibility and arrangement within the cell membrane. It was shown that the increase in the ligand binding of glycosylated EGFR is mediated by the interaction between the two glycans attached to the growth factor binding subdomains resulting in stabilization of the growth factor binding site. Persistent hydrogen bonds’ formation between the glycans and EGFR contributes to proper folding and reduced flexibly of the glycosylated receptor. Assembly of the cell-integrated EGFR and its relative distance from the membrane are acquired by the lift-up action of the attached glycans. These findings can be used as a framework for implementation of computational techniques to obtain atomistic details of protein glycosylation as one of the most important areas of structural biology. [ABSTRACT FROM AUTHOR]

Epidermal Growth Factor Receptor (EGFR) is a glycosylated tyrosine kinase receptor associated with several cancers. EGFR plays an important role in cancer therapy and inspired several experimental and computational (molecular dynamics simulation) studies to investigate its function and dynamics. N-glycosylation is a critical aspect of EGFR functioning that was mainly unexplained until recently due to the challenges in obtaining and analysis of the structural data involving the glycan moieties. Latest simulations of glycosylated EGFR suggest atomistic mechanisms underlying the experimentally proposed functions of N-glycans in: EGFR increased ligand binding, reduced flexibility and arrangement within the cell membrane. It was shown that the increase in the ligand binding of glycosylated EGFR is mediated by the interaction between the two glycans attached to the growth factor binding subdomains resulting in stabilization of the growth factor binding site. Persistent hydrogen bonds’ formation between the glycans and EGFR contributes to proper folding and reduced flexibly of the glycosylated receptor. Assembly of the cell-integrated EGFR and its relative distance from the membrane are acquired by the lift-up action of the attached glycans. These findings can be used as a framework for implementation of computational techniques to obtain atomistic details of protein glycosylation as one of the most important areas of structural biology. [ABSTRACT FROM AUTHOR]

Heterocephalus glaber , known as the Naked mole-rat, has an extraordinary immunity to Alzheimer's disease. The pathological hallmark of Alzheimer's disease is cerebral accumulations of plaques, consisting of self-aggregated amyloid beta peptides. Homo sapiens and H. glaber amyloid beta peptides are different in only one amino acid. Herein, computational structural analyses were carried out to determine whether plaque development in H. glaber is prevented by the replacement of His13 with Arg13 in the amyloid beta peptide. AlphaFold2 was used to predict the structure of the H. glaber amyloid beta peptide. HADDOCK and Hex were used to self-dock the peptides and dock ions on peptides, respectively. Illustrations were made by PyMol and ChimeraX. Using VMD, we calculated the radius of gyration. The phylogenetic analysis was conducted by Mega. The results showed an accurate structure with two alpha helices separated by a short coil for H. glaber . Self-docking of the two amyloid beta peptides demonstrated a globular conformation in the H. glaber dimer, implying the unlikeliness of amyloid beta peptides' self-aggregation to form fibrillar structures. This conformational state resulted in lower electrostatic energy compared to H. sapiens , contributing to H. glaber's lower tendency for fibril and, ultimately, plaque formation. Phylogenetic analysis confirmed that amyloid precursor protein is highly conserved in each taxon of rodentia and primata. This study provides insight into the connection between the structure of H. glaber amyloid beta and its plaque formation properties, showing that the Arg13 in H. glaber leads to fibril instability, and might prevent senile plaque accumulation., Competing Interests: The authors declare no competing interests.

The human epidermal growth factor receptor (EGFR/ErbB) family consists of four members (ErbB1-4) and belongs to the superfamily of receptor tyrosine kinases (RTKs). The ErbB family members participate in multiple cellular pathways and are the key players in several cancers (brain, breast, lung etc.). Activation of these family members depends on their extracellular domains forming back-to-back hetero/homo dimers. Moreover, dimers are glycosylated, which is a crucial post-translational modification that affects the conformation and function of the protein. Here, molecular modeling and molecular docking are used to comprehensively investigate the dimerization mechanism in glycosylated back-to-back active dimer formation in the entire ErbB receptors for the first time. Results showed that 21 out of 37 clusters of active back-to-back dimers formed by all family members are through heterodimerization. Including; ErbB1-ErbB3/ErbB4, ErbB2-ErbB3/ErbB4 and ErbB3-ErbB4. Ranking ErbB2-ErbB3 as the most stabilized back-to-back dimeric construct. While glycan arrangements favor both homo/hetero dimerization at the dimeric interfaces, it promotes heterodimerization by stabilizing and packing the ligand binding sites of EGFR and ErbB2 respectively. These findings pave the path to future heterodimeric interface/glycan targeting rational anti-cancer drug designs for ErbB receptors., Competing Interests: The authors declare no competing interests.