Insights into amyotrophic lateral sclerosis linked Pro525Arg mutation in the fused in sarcoma protein through <i>in silico</i> analysis and molecular dynamics simulation

Chatterjee, Sompriya; Salimi, Abbas; Lee, Jin Yong

doi:10.1080/07391102.2020.1794967

Cited by 11 publications

(6 citation statements)

References 74 publications

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Section: Results and Discussionmentioning

confidence: 99%

“…Hydrogen bonding is the most significant noncovalent interaction which has a crucial job in the overall stability and molecular recognition abilities of a peptide structure. 55 To assess the functions of histidine residues in δδ, εε, εδ, and δε tautomeric isomers, hydrogen-bond populations connected to histidine amino acids were collected and presented in the Supporting Information (Table S1). The number of hydrogenbond populations was dramatically different in the four tau isomers, indicating the histidine tautomeric states can affect structural and accumulation features of the tau monomer.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau_267–312 Monomer

Chatterjee

Salimi

Lee

2020

ACS Chem. Neurosci.

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Histidine tautomerism is considered a crucial component that affects the constitutional and accumulation characteristics of the tau 267−312 monomer in the neutral condition, which are connected with the pathobiology of Alzheimer's disease (AD). Interpreting the organizational characteristics and accumulation procedure is a challenging task because two tautomeric conformations (the N ε −H or N δ −H tautomer) can occur in the open neutral condition. In the current work, replica-exchange molecular dynamics (REMD) simulations were performed to investigate the structural properties of the tau 267−312 monomer considering the histidine tautomeric effect. Based on the simulation outcomes, the histidine 268 (H268) (δ)− H299 (δ) (δδ) isomer had the highest β-sheet content with a value of 26.2%, which acquires a sheet-governing toxic conformer with the first abundant conformational state of 22.6%. In addition, δδ displayed notable antiparallel βsheets between lysine 8 (K8)−asparagine 13 (N13) and valine 40 (V40)−tyrosine 44 (Y44) as well as between K32−H33 and V40−Y44 (β-meander supersecondary structure), indicating this tautomeric isomer may exist to stimulate tau oligomerization. Furthermore, H299 was found to play an essential role in the structural stabilization of the δδ isomer compared with H268. The present research will aid in obtaining insight into the organizational and accumulation properties of tau protein in the presence of histidine tautomerism to control AD.

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Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau_267–312 Monomer

Chatterjee

Salimi

Lee

2020

ACS Chem. Neurosci.

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“…Due to its relevance in liquid–liquid phase separation (LLPS) and fibril formation, the FUS-LC domain has been the subject of several experimental biophysical studies ,− and simulations. − The experimental findings that are relevant to our study may be summarized as follows: (i) A combination of fluorescence microscopy and solution-state NMR of a truncated version (residues 1–163) of FUS-LC indicate that it is devoid of persistent structure, both in the monomer as well as in the liquid-droplet state . In contrast to a previous report based on X-ray crystallography and negative stain transmission electron microscopy (TEM) experiments, no signatures of hydrogel formation were immediately apparent in the condensed phase.…”

mentioning

confidence: 80%

Sequence Determines the Switch in the Fibril Forming Regions in the Low-Complexity FUS Protein and Its Variants

Kumar

Chakraborty

Mugnai

et al. 2021

J. Phys. Chem. Lett.

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Residues spanning distinct regions of the low-complexity domain of the RNA-binding protein, Fused in Sarcoma (FUS-LC), form fibril structures with different core morphologies. Solid-state NMR experiments show that the 214-residue FUS-LC forms a fibril with an S-bend (core-1, residues 39–95), while the rest of the protein is disordered. In contrast, the fibrils of the C-terminal variant (FUS-LC-C; residues 111–214) have a U-bend topology (core-2, residues 112–150). Absence of the U-bend in FUS-LC implies that the two fibril cores do not coexist. Computer simulations show that these perplexing findings could be understood in terms of the population of sparsely populated fibril-like excited states in the monomer. The propensity to form core-1 is higher compared to core-2. We predict that core-2 forms only in truncated variants that do not contain the core-1 sequence. At the monomer level, sequence-dependent enthalpic effects determine the relative stabilities of the core-1 and core-2 topologies.

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“…46 Collectively, our findings lead us to suggest that under less polar conditions, intramolecular π−π donor−acceptor interactions between the LuTex core and the celecoxib moiety are reduced, thus favoring a type II photodynamic pathway that produces 1 The properties of LuCXB in two different solvent media were quantified via root-mean-square deviation (RMSD), rootmean-square fluctuation (RMSF), and average distance criteria. 48,49 To gain insights into the flexible nature of the molecule in both solvents, the RMSD of LuCXB was calculated from the trajectories generated after equilibration. The calculated average RMSD (⟨RMSD⟩) values of LuCXB in H 2 O and DMSO were found to be 2.38 and 2.44 nm, respectively (Figure S31a).…”

Section: ■ Introductionmentioning

confidence: 99%

Lutetium Texaphyrin–Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent

An,

Lv,

Chau

et al. 2024

J. Am. Chem. Soc.

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Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor− acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O 2 −• ) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@ LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.

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Insights into amyotrophic lateral sclerosis linked Pro525Arg mutation in the fused in sarcoma protein through in silico analysis and molecular dynamics simulation

Cited by 11 publications

References 74 publications

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau_267–312 Monomer

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau_267–312 Monomer

Sequence Determines the Switch in the Fibril Forming Regions in the Low-Complexity FUS Protein and Its Variants

Lutetium Texaphyrin–Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent

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Insights into amyotrophic lateral sclerosis linked Pro525Arg mutation in the fused in sarcoma protein through in silico analysis and molecular dynamics simulation

Cited by 11 publications

References 74 publications

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau267–312 Monomer

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau267–312 Monomer

Sequence Determines the Switch in the Fibril Forming Regions in the Low-Complexity FUS Protein and Its Variants

Lutetium Texaphyrin–Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent

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Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau_267–312 Monomer

Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau_267–312 Monomer