hIAPP-Amyloid-Core Derived <scp>d</scp>-Peptide Prevents hIAPP Aggregation and Destabilizes Its Protofibrils

Zinc finger antiviral protein (ZAP) is a host antiviral factor that selectively inhibits the replication of a variety of viruses. ZAP recognizes the CG-enriched RNA sequences and activates the viral RNA degradation machinery. In this work, we investigated the dynamics of a ZAP/RNA complex and computed the energetics of mutations in ZAP that affect its binding to the viral RNA. The crystal structure of a mouse-ZAP/RNA complex showed that RNA interacts with the zinc finger 2 (ZF2) and ZF3 domains. However, we found that due to the dynamic behavior of the single-stranded RNA, the terminal nucleotides C1 and G2 of RNA change their positions from the ZF3 to the ZF1 domain. Moreover, the electrostatic interactions between the zinc ions and the viral RNA provide further stability to the ZAP/RNA complex. We also provide structural and thermodynamic evidence for seven residue pairs (C1–Arg74, C1–Arg179, G2–Arg74, U3–Lys76, C4–Lys76, G5–Arg95, and U6–Glu204) that show favorable ZAP/RNA interactions, although these interactions were not observed in the ZAP/RNA crystal structure. Consistent with the observations from the mouse-ZAP/RNA crystal structure, we found that four residue pairs (C4–Lys89, C4–Leu90, C4–Tyr108, and G5–Lys107) maintained stable interactions in MD simulations. Based on experimental mutagenesis studies and our residue-level interaction analysis, we chose seven residues (Arg74, Lys76, Lys89, Arg95, Lys107, Tyr108, and Arg179) for individual alanine mutations. In addition, we studied mutations in those residues that are only observed in the crystal structures as interacting with RNA (Tyr98, Glu148, and Arg170). Out of these 10 mutations, we found that the Ala mutation in each of the five residues Arg74, Lys76, Lys89, Lys107, and Glu148 significantly reduced the binding affinity of ZAP to RNA.

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“…A hydrogen bond was considered to form when the donor–acceptor distance was within 3.5 Å and the donor–acceptor–hydrogen angle was within 45°. − …”

Section: Methodsmentioning

confidence: 99%

Role of Dynamics and Mutations in Interactions of a Zinc Finger Antiviral Protein with CG-rich Viral RNA

Pal

Kumar

Vashisth

2023

J. Chem. Inf. Model.

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“…Hence, the four systems resulted in an additional 11.92 (1.6 of unbiased and 10.32 of biased) μs of simulations. The PMF of the hIAPP dimer in pure water was plotted using the results obtained in a previous study …”

Section: Simulation Methodsmentioning

confidence: 99%

“…The PMF of the hIAPP dimer in pure water was plotted using the results obtained in a previous study. 108…”

Section: Iiii Simulation Analysismentioning

confidence: 99%

Disparate Effect of Hybrid Peptidomimetics Containing Isomers of Aminobenzoic Acid on hIAPP Aggregation

Roy

Paul

2022

J. Phys. Chem. B

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The abnormal misfolding of human islet amyloid polypeptide (hIAPP) in pancreatic β-cells is implicated in the progression of type II diabetes (T2D). With the prevalence of T2D increasing worldwide, preventing the aggregation of hIAPP has been recognized as a promising therapeutic strategy to control this disease. Recently, a class of novel conformationally restricted β-sheet breaker hybrid peptidomimetics (BSBHps) was found to demonstrate efficient inhibitory ability toward amyloid formation of hIAPP. One (Ile26) or more (Gly24 and Ile26) residues in these six-membered peptide sequences, which have been extracted from the amyloidogenic core of hIAPP, N 22 FGAIL 27 , are substituted by three different isomers of the conformationally restricted aromatic amino acid, i.e., aminobenzoic acid (β, γ, and δ), to generate these BSBHps. The presence of the nonproteinogenic aminobenzoic acid moiety renders the BSBHps to be more stable toward proteolytic degradation. The different isomeric BSBHps exhibit contrasting influence on the self-assembly of hIAPP. The BSBHps containing βand γ-aminobenzoic acid can sufficiently prevent hIAPP aggregation, but those with the δ-aminobenzoic group stabilize the β-sheet-rich aggregate of hIAPP. The difference in the angle between the amino and carboxyl groups in the isomers of the aminobenzoic moiety causes the BSBHps to attain discrete conformation and hence leads to variation in their binding preference with hIAPP and ultimately their inhibitory potency. This guides the pathway for the dissimilar effect of BSBHps on peptide aggregation and, therefore, provides insights into the design considerations for novel drugs against T2D.

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“…), − and peptide-based inhibitors (e.g., hIAPP amyloid core derived d-peptide, etc.) . The motivations are to interfere the amyloid aggregation through competing the amyloid peptide interactions by establishing hydrogen bonds, hydrophobic interactions, and π-stacking between the amyloid peptides and inhibitors as the mechanisms revealed by molecular dynamics simulations. − ,− Among them, helix mimetic is an appealing small molecular strategy for the inhibition of amyloid aggregation. − The basic idea of helix mimetics is to reproduce the side chain at residues i , i + 3/ i + 4, and i + 7 of a natural α-helix and modulate protein–protein interactions .…”

Section: Introductionmentioning

confidence: 99%

“…. The motivations are to interfere the amyloid aggregation through competing the amyloid peptide interactions by establishing hydrogen bonds, hydrophobic interactions, and π-stacking between the amyloid peptides and inhibitors as the mechanisms revealed by molecular dynamics simulations. − ,− Among them, helix mimetic is an appealing small molecular strategy for the inhibition of amyloid aggregation. − The basic idea of helix mimetics is to reproduce the side chain at residues i , i + 3/ i + 4, and i + 7 of a natural α-helix and modulate protein–protein interactions . A library of helix mimetics has been synthesized and applied to inhibit protein aggregation, including hIAPP, , Alzheimer’s disease-related amyloid-β (Aβ) protein, , and cancer-associated mutant p53 protein .…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic/Hydrophilic Ratio of Amphiphilic Helix Mimetics Determines the Effects on Islet Amyloid Polypeptide Aggregation

Tang

Sun

Ding

2022

J. Chem. Inf. Model.

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Amyloid depositions of human islet amyloid polypeptides (hIAPP) are associated with type II diabetes (T2D) impacting millions of people globally. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Helix mimetics, which modulate the protein–protein interaction by mimicking the side chain residues of a natural α-helix, were found to be a promising strategy for inhibiting hIAPP aggregation. Here, we applied molecular dynamics simulations to investigate two helix mimetics reported to have opposite effects on hIAPP aggregation in solution, the oligopyridylamide-based scaffold 1e promoted, whereas naphthalimide-appended oligopyridylamide scaffold DM 1 inhibited the aggregation of hIAPP in solution. We found that 1e promoted hIAPP aggregation because of the recruiting effects through binding with the N-termini of hIAPP peptides. In contrast, DM 1 with a higher hydrophobic/hydrophilic ratio effectively inhibited hIAPP aggregation by strongly binding with the C-termini of hIAPP peptides, which competed for the interpeptide contacts between amyloidogenic regions in the C-termini and impaired the fibrillization of hIAPP. Structural analyses revealed that DM 1 formed the core of hIAPP-DM 1 complexes and stabilized the off-pathway oligomers, whereas 1e formed the corona outside the hIAPP-1e complexes and remained active in recruiting free hIAPP peptides. The distinct interaction mechanisms of DM 1 and 1e, together with other reported potent antagonists in the literature, emphasized the effective small molecule-based amyloid inhibitors by disrupting peptide interactions that should reach a balanced hydrophobic/hydrophilic ratio, providing a viable and generic strategy for the rational design of novel anti-amyloid nanomedicine.

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hIAPP-Amyloid-Core Derived d-Peptide Prevents hIAPP Aggregation and Destabilizes Its Protofibrils

Cited by 12 publications

References 114 publications

Role of Dynamics and Mutations in Interactions of a Zinc Finger Antiviral Protein with CG-rich Viral RNA

Role of Dynamics and Mutations in Interactions of a Zinc Finger Antiviral Protein with CG-rich Viral RNA

Disparate Effect of Hybrid Peptidomimetics Containing Isomers of Aminobenzoic Acid on hIAPP Aggregation

Hydrophobic/Hydrophilic Ratio of Amphiphilic Helix Mimetics Determines the Effects on Islet Amyloid Polypeptide Aggregation

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