The molecular mechanism of structural changes in the antimicrobial peptide CM15 upon complex formation with drug molecule suramin: a computational analysis

Gergely Kohut , Adam Sieradzan , Ferenc Zsila , Tünde Juhász , Szilvia Bösze , Józef Adam Liwo , Sergey Samsonov , Tamás Beke-Somfai

Abstract

Dynamic increase of resistant bacterial infectious diseases continuously requires development of novel compounds against them. The molecular level understanding of the mechanism and interactions of natural host-defense peptides or antimicrobial peptides (AMPs) is an important step towards rational design and development of compounds inspired by their function. A particular set of these peptides have disordered structure, the ordering of which may modify their antimicrobial properties. Recent experiments demonstrate that such conformational transitions of AMPs could be mediated by the presence of small organic compounds, such as approved drug molecules. However, the molecular mechanisms underlying these structural changes are unclear. In this study, we apply molecular docking and molecular dynamics-based approaches to rigorously analyze the interactions between the drug suramin and the AMP CM15, a synthetic unstructured hybrid peptide. We characterize the energetic properties of putative CM15–suramin complexes revealing particular impacts of CM15 residues as well as the parts of suramin on these interactions. We find that α-helical content of the peptide is increased in the presence of suramin, which is in agreement with the experimental data. Kinetics analysis from canonical molecular dynamics and metadynamics simulations suggest that the effect of suramin does not promote the formation of α-helix but rather results from its ability to stabilize the α-helical population in the conformational pool of the peptide. Potentially, understanding the physico-chemical basis underlying the interactions between drug molecules and disordered AMPs will prove useful in strategies for antimicrobial compound development. Further on, the given computational protocol for the analysis of such flexible systems provide a basis for future theoretical investigation of similar biomolecular complexes.
Author Gergely Kohut - [Magyar Tudomanyos Akademia]
Gergely Kohut,,
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, Adam Sieradzan (FCh / DTCh / LMM)
Adam Sieradzan,,
- Laboratory of Molecular Modeling
, Ferenc Zsila - [Magyar Tudomanyos Akademia]
Ferenc Zsila,,
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, Tünde Juhász - [Magyar Tudomanyos Akademia]
Tünde Juhász,,
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, Szilvia Bösze
Szilvia Bösze,,
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, Józef Adam Liwo (FCh / DTCh / LMM)
Józef Adam Liwo,,
- Laboratory of Molecular Modeling
, Sergey Samsonov (FCh / DTCh / LMM)
Sergey Samsonov,,
- Laboratory of Molecular Modeling
, Tamás Beke-Somfai - [Magyar Tudomanyos Akademia]
Tamás Beke-Somfai,,
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Journal seriesPhysical Chemistry Chemical Physics, ISSN 1463-9076, (N/A 100 pkt)
Issue year2019
Vol21
No20
Pages10644-10659
Publication size in sheets0.75
ASJC Classification1606 Physical and Theoretical Chemistry; 3100 General Physics and Astronomy
DOIDOI:10.1039/C9CP00471H
Languageen angielski
LicenseRepository; author's final; Uznanie Autorstwa - Na Tych Samych Warunkach (CC-BY-SA); after publication
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Kohut_Gergely_The_Molecular_Mechanism_of_Structural_Changes_in_the_Antimicrobial_Peptide_CM15_Upon_Complex_Formation_with_Drug_Molecule_Suramin:_a_Computational_Analysis_2019.pdf 17.27 MB
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 17-01-2020, ArticleFromJournal
Publication indicators WoS Citations = 1; Scopus Citations = 1; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.117; WoS Impact Factor: 2018 = 3.567 (2) - 2018=3.963 (5)
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LicencjaUtwór jest udostępniany na licencji Creative Commons Uznanie autorstwa-Na tych samych warunkach 4.0 Międzynarodowe (CC BY-SA 4.0) https://creativecommons.org/licenses/by-sa/4.0/
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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