Multiscale modeling of innate immune receptors: Endotoxin recognition and regulation by host defense peptides

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Multiscale modeling of innate immune receptors: Endotoxin recognition and regulation by host defense peptides
Title:
Multiscale modeling of innate immune receptors: Endotoxin recognition and regulation by host defense peptides
Other Titles:
Pharmacological Research
Publication Date:
24 July 2019
Citation:
Daniel A. Holdbrook, Roland G. Huber, Jan K. Marzinek, Astrid Stubbusch, Artur Schmidtchen, Peter J. Bond, Multiscale modeling of innate immune receptors: Endotoxin recognition and regulation by host defense peptides, Pharmacological Research, Volume 147, 2019, 104372, ISSN 1043-6618, https://doi.org/10.1016/j.phrs.2019.104372.
Abstract:
The innate immune system provides a first line of defense against foreign microorganisms, and is typified by the Toll-like receptor (TLR) family. TLR4 is of particular interest, since over-stimulation of its pathway by excess lipopolysaccharide (LPS) molecules from the outer membranes of Gram-negative bacteria can result in sepsis, which causes millions of deaths each year. In this review, we outline our use of molecular simulation approaches to gain a better understanding of the determinants of LPS recognition, towards the search for novel immunotherapeutics. We first describe how atomic-resolution simulations have enabled us to elucidate the regulatory conformational changes in TLR4 associated with different LPS analogues, and hence a means to rationalize experimental structure-activity data. Furthermore, multiscale modelling strategies have provided a detailed description of the thermodynamics and intermediate structures associated with the entire TLR4 relay – which consists of a number of transient receptor/coreceptor complexes – allowing us trace the pathway of LPS transfer from bacterial membranes to the terminal receptor complex at the plasma membrane surface. Finally, we describe our efforts to leverage these computational models, in order to elucidate previously undisclosed anti-inflammatory mechanisms of endogenous host-defense peptides found in wounds. Collectively, this work represents a promising avenue for the development of novel anti-septic treatments, inspired by nature’s innate defense strategies.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
This research is supported by core fundinng from the Bioinformatics Institute, ARES.
Description:
ISSN:
1043-6618
1096-1186
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