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Computational analysis of complement inhibitor compstatin using molecular dynamics

The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compst...

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Detalles Bibliográficos
Autores principales: Devaurs, Didier, Antunes, Dinler A., Kavraki, Lydia E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851517/
https://www.ncbi.nlm.nih.gov/pubmed/32789582
http://dx.doi.org/10.1007/s00894-020-04472-8
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author Devaurs, Didier
Antunes, Dinler A.
Kavraki, Lydia E.
author_facet Devaurs, Didier
Antunes, Dinler A.
Kavraki, Lydia E.
author_sort Devaurs, Didier
collection PubMed
description The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compstatin analogs have been created, with improved inhibitory potency. A recent analog is being developed as a candidate drug against several pathological conditions, including COVID-19. However, the reasons behind its higher potency and increased binding affinity to complement proteins are not fully clear. This computational study highlights the mechanistic properties of several compstatin analogs, thus complementing previous experimental studies. We perform molecular dynamics simulations involving six analogs alone in solution and two complexes with compstatin bound to complement component 3. These simulations reveal that all the analogs we consider, except the original compstatin, naturally adopt a pre-bound conformation in solution. Interestingly, this set of analogs adopting a pre-bound conformation includes analogs that were not known to benefit from this behavior. We also show that the most recent compstatin analog (among those we consider) forms a stronger hydrogen bond network with its complement receptor than an earlier analog.
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spelling pubmed-88515172022-02-18 Computational analysis of complement inhibitor compstatin using molecular dynamics Devaurs, Didier Antunes, Dinler A. Kavraki, Lydia E. J Mol Model Original Paper The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compstatin analogs have been created, with improved inhibitory potency. A recent analog is being developed as a candidate drug against several pathological conditions, including COVID-19. However, the reasons behind its higher potency and increased binding affinity to complement proteins are not fully clear. This computational study highlights the mechanistic properties of several compstatin analogs, thus complementing previous experimental studies. We perform molecular dynamics simulations involving six analogs alone in solution and two complexes with compstatin bound to complement component 3. These simulations reveal that all the analogs we consider, except the original compstatin, naturally adopt a pre-bound conformation in solution. Interestingly, this set of analogs adopting a pre-bound conformation includes analogs that were not known to benefit from this behavior. We also show that the most recent compstatin analog (among those we consider) forms a stronger hydrogen bond network with its complement receptor than an earlier analog. Springer Berlin Heidelberg 2020-08-12 2020 /pmc/articles/PMC8851517/ /pubmed/32789582 http://dx.doi.org/10.1007/s00894-020-04472-8 Text en © Springer-Verlag GmbH Germany, part of Springer Nature 2020 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Original Paper
Devaurs, Didier
Antunes, Dinler A.
Kavraki, Lydia E.
Computational analysis of complement inhibitor compstatin using molecular dynamics
title Computational analysis of complement inhibitor compstatin using molecular dynamics
title_full Computational analysis of complement inhibitor compstatin using molecular dynamics
title_fullStr Computational analysis of complement inhibitor compstatin using molecular dynamics
title_full_unstemmed Computational analysis of complement inhibitor compstatin using molecular dynamics
title_short Computational analysis of complement inhibitor compstatin using molecular dynamics
title_sort computational analysis of complement inhibitor compstatin using molecular dynamics
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851517/
https://www.ncbi.nlm.nih.gov/pubmed/32789582
http://dx.doi.org/10.1007/s00894-020-04472-8
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