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

Holdbrook, Daniel A. ; Huber, Roland G. ; Marzinek, J. K. ; Stubbusch, Astrid ; Schmidtchen, A. LU and Bond, Peter J. (2019) In Pharmacological Research 147.
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Cluster of differentiation 14 (CD14), Molecular dynamics (MD) simulation, Multiscale modelling, Sepsis, Thrombin-derived C-terminal fragments, Toll-like receptor 4 (TLR4)
in
Pharmacological Research
volume
147
article number
104372
publisher
Academic Press
external identifiers
  • scopus:85069838548
ISSN
1043-6618
DOI
10.1016/j.phrs.2019.104372
language
English
LU publication?
yes
id
8b8d0f9c-e030-4762-9000-7f6af48ff7d3
date added to LUP
2019-08-30 10:54:57
date last changed
2019-09-04 04:49:39
@article{8b8d0f9c-e030-4762-9000-7f6af48ff7d3,
  abstract     = {<p>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.</p>},
  author       = {Holdbrook, Daniel A. and Huber, Roland G. and Marzinek, J. K. and Stubbusch, Astrid and Schmidtchen, A. and Bond, Peter J.},
  issn         = {1043-6618},
  language     = {eng},
  publisher    = {Academic Press},
  series       = {Pharmacological Research},
  title        = {Multiscale modeling of innate immune receptors : Endotoxin recognition and regulation by host defense peptides},
  url          = {http://dx.doi.org/10.1016/j.phrs.2019.104372},
  doi          = {10.1016/j.phrs.2019.104372},
  volume       = {147},
  year         = {2019},
}