Dataset Information

Insights into Interactions between Interleukin-6 and Dendritic Polyglycerols.

ABSTRACT: Interleukin-6 (IL-6) is involved in physiological and pathological processes. Different pharmacological agents have been developed to block IL-6 deleterious effects and to recover homeostatic IL-6 signaling. One of the proposed nanostructures in pre-clinical investigations which reduced IL-6 concentrations is polyglycerol dendrimer, a nano-structure with multiple sulfate groups. The aim of the present study was to uncover the type of binding between critical positions in the human IL-6 structure available for binding dPGS and compare it with heparin sulfate binding. We studied these interactions by performing docking simulations of dPGS and heparins with human IL-6 using AutoDock Vina. These molecular docking analyses indicate that the two ligands have comparable affinities for the positively charged positions on the surface of IL-6. All-atom molecular dynamics simulations (MD) employing Gromacs were used to explore the binding sites and binding strengths. Results suggest two major binding sites and show that the strengths of binding are similar for heparin and dPGS (-5.5-6.4 kcal/ mol). dPGS or its analogs could be used in the therapeutic intervention in sepsis and inflammatory disorders to reduce unbound IL-6 in the plasma or tissues and its binding to the receptors. We propose that analogs of dPGS could specifically block IL-6 binding in the desired signaling mode and would be valuable new probes to establish optimized therapeutic intervention in inflammation.

SUBMITTER: Sanader Marsic Z

PROVIDER: S-EPMC7957513 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Insights into Interactions between Interleukin-6 and Dendritic Polyglycerols.

Sanader Maršić Željka Ž Maysinger Dušica D Bonačić-Kouteckỳ Vlasta V

International journal of molecular sciences 20210228 5

Interleukin-6 (IL-6) is involved in physiological and pathological processes. Different pharmacological agents have been developed to block IL-6 deleterious effects and to recover homeostatic IL-6 signaling. One of the proposed nanostructures in pre-clinical investigations which reduced IL-6 concentrations is polyglycerol dendrimer, a nano-structure with multiple sulfate groups. The aim of the present study was to uncover the type of binding between critical positions in the human IL-6 structure ...[more]

PMID: 33670858

Similar Datasets

Project description:The aggregation of amyloid-? (A?) peptides into senile plaques is a hallmark of Alzheimer's disease (AD) and is hypothesized to be the primary cause of AD related neurodegeneration. Previous studies have shown the ability of curcumin to both inhibit the aggregation of A? peptides into oligomers or fibrils and reduce amyloids in vivo. Despite the promise of curcumin and its derivatives to serve as diagnostic, preventative, and potentially therapeutic AD molecules, the mechanism by which curcumin and its derivatives bind to and inhibit A? fibrils' formation remains elusive. Here, we investigated curcumin and a set of curcumin derivatives in complex with a hexamer peptide model of the A?1-42 fibril using nearly exhaustive docking, followed by multi-ns molecular dynamics simulations, to provide atomistic-detail insights into the molecules' binding and inhibitory properties. In the vast majority of the simulations, curcumin and its derivatives remain firmly bound in complex with the fibril through primarily three different principle binding modes, in which the molecules interact with residue domain 17LVFFA21, in line with previous experiments. In a small subset of these simulations, the molecules partly dissociate the outermost peptide of the A?1-42 fibril by disrupting ?-sheets within the residue domain 12VHHQKLVFF20. A comparison between binding modes leading or not leading to partial dissociation of the outermost peptide suggests that the latter is attributed to a few subtle key structural and energetic interaction-based differences. Interestingly, partial dissociation appears to be either an outcome of high affinity interactions or a cause leading to high affinity interactions between the molecules and the fibril, which could partly serve as a compensation for the energy loss in the fibril due to partial dissociation. In conjunction with this, we suggest a potential inhibition mechanism of ??1-42 aggregation by the molecules, where the partially dissociated 16KLVFF20 domain of the outermost peptide could either remain unstructured or wrap around to form intramolecular interactions with the same peptide's 29GAIIG33 domain, while the molecules could additionally act as a patch against the external edge of the second outermost peptide's 16KLVFF20 domain. Thereby, individually or concurrently, these could prohibit fibril elongation.

Dataset Information

Insights into Interactions between Interleukin-6 and Dendritic Polyglycerols.

Publications

Insights into Interactions between Interleukin-6 and Dendritic Polyglycerols.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets