Conformational Stability Study of a Therapeutic Peptide Plectasin Using Molecular Dynamics Simulations in Combination with NMR

Sowmya Indrakumar*, Matja Zalar, Christin Pohl, Allan Nørgaard, Werner Streicher, Pernille Harris, Alexander P. Golovanov, Günther H.J. Peters

*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

Plectasin is a small, cysteine-rich peptide antibiotic which belongs to the class of antimicrobial peptides and has potential antibacterial activity against various Gram-positive bacteria. In the current study, the effect of pH and ionic strength (NaCl) on the conformational stability of plectasin variants has been investigated. At all physiochemical conditions, peptide secondary structures are intact throughout simulations. However, flexibility increases with pH because of the change in electrostatics around the distinct anionic tetrapeptide (9-12) stretch. Furthermore, plectasin interactions with NaCl were measured by determining the preferential interaction coefficients, Γ23. Generally, wild-type plectasin has higher preference for sodium ions as 9ASP is mutated in other variants. Overall, the Γ23 trend with pH for the two salt conditions remain the same for all variants predominately having accumulation of sodium ions around 10GLU and 12ASP. Insignificant changes in the overall peptide conformational stability are in agreement with the fact that plectasin has three cystines. Thermodynamic integration molecular dynamics simulations supplemented with nuclear magnetic resonance were employed to determine the degree of involvement of three different cystines to the overall structural integrity of the peptide. Both methods show the same order of cystine reduction and complete unfolding is observed only upon reduction of all cystines.
Original languageEnglish
JournalJournal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical
Volume123
Issue number23
Pages (from-to)4867-4877
Number of pages11
ISSN1520-6106
DOIs
Publication statusPublished - 2019

Cite this

Indrakumar, Sowmya ; Zalar, Matja ; Pohl, Christin ; Nørgaard, Allan ; Streicher, Werner ; Harris, Pernille ; Golovanov, Alexander P. ; Peters, Günther H.J. / Conformational Stability Study of a Therapeutic Peptide Plectasin Using Molecular Dynamics Simulations in Combination with NMR. In: Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical. 2019 ; Vol. 123, No. 23. pp. 4867-4877.
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title = "Conformational Stability Study of a Therapeutic Peptide Plectasin Using Molecular Dynamics Simulations in Combination with NMR",
abstract = "Plectasin is a small, cysteine-rich peptide antibiotic which belongs to the class of antimicrobial peptides and has potential antibacterial activity against various Gram-positive bacteria. In the current study, the effect of pH and ionic strength (NaCl) on the conformational stability of plectasin variants has been investigated. At all physiochemical conditions, peptide secondary structures are intact throughout simulations. However, flexibility increases with pH because of the change in electrostatics around the distinct anionic tetrapeptide (9-12) stretch. Furthermore, plectasin interactions with NaCl were measured by determining the preferential interaction coefficients, Γ23. Generally, wild-type plectasin has higher preference for sodium ions as 9ASP is mutated in other variants. Overall, the Γ23 trend with pH for the two salt conditions remain the same for all variants predominately having accumulation of sodium ions around 10GLU and 12ASP. Insignificant changes in the overall peptide conformational stability are in agreement with the fact that plectasin has three cystines. Thermodynamic integration molecular dynamics simulations supplemented with nuclear magnetic resonance were employed to determine the degree of involvement of three different cystines to the overall structural integrity of the peptide. Both methods show the same order of cystine reduction and complete unfolding is observed only upon reduction of all cystines.",
author = "Sowmya Indrakumar and Matja Zalar and Christin Pohl and Allan N{\o}rgaard and Werner Streicher and Pernille Harris and Golovanov, {Alexander P.} and Peters, {G{\"u}nther H.J.}",
year = "2019",
doi = "10.1021/acs.jpcb.9b02370",
language = "English",
volume = "123",
pages = "4867--4877",
journal = "Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical",
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Indrakumar, S, Zalar, M, Pohl, C, Nørgaard, A, Streicher, W, Harris, P, Golovanov, AP & Peters, GHJ 2019, 'Conformational Stability Study of a Therapeutic Peptide Plectasin Using Molecular Dynamics Simulations in Combination with NMR', Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical, vol. 123, no. 23, pp. 4867-4877. https://doi.org/10.1021/acs.jpcb.9b02370

Conformational Stability Study of a Therapeutic Peptide Plectasin Using Molecular Dynamics Simulations in Combination with NMR. / Indrakumar, Sowmya; Zalar, Matja; Pohl, Christin; Nørgaard, Allan; Streicher, Werner; Harris, Pernille; Golovanov, Alexander P.; Peters, Günther H.J.

In: Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical, Vol. 123, No. 23, 2019, p. 4867-4877.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Conformational Stability Study of a Therapeutic Peptide Plectasin Using Molecular Dynamics Simulations in Combination with NMR

AU - Indrakumar, Sowmya

AU - Zalar, Matja

AU - Pohl, Christin

AU - Nørgaard, Allan

AU - Streicher, Werner

AU - Harris, Pernille

AU - Golovanov, Alexander P.

AU - Peters, Günther H.J.

PY - 2019

Y1 - 2019

N2 - Plectasin is a small, cysteine-rich peptide antibiotic which belongs to the class of antimicrobial peptides and has potential antibacterial activity against various Gram-positive bacteria. In the current study, the effect of pH and ionic strength (NaCl) on the conformational stability of plectasin variants has been investigated. At all physiochemical conditions, peptide secondary structures are intact throughout simulations. However, flexibility increases with pH because of the change in electrostatics around the distinct anionic tetrapeptide (9-12) stretch. Furthermore, plectasin interactions with NaCl were measured by determining the preferential interaction coefficients, Γ23. Generally, wild-type plectasin has higher preference for sodium ions as 9ASP is mutated in other variants. Overall, the Γ23 trend with pH for the two salt conditions remain the same for all variants predominately having accumulation of sodium ions around 10GLU and 12ASP. Insignificant changes in the overall peptide conformational stability are in agreement with the fact that plectasin has three cystines. Thermodynamic integration molecular dynamics simulations supplemented with nuclear magnetic resonance were employed to determine the degree of involvement of three different cystines to the overall structural integrity of the peptide. Both methods show the same order of cystine reduction and complete unfolding is observed only upon reduction of all cystines.

AB - Plectasin is a small, cysteine-rich peptide antibiotic which belongs to the class of antimicrobial peptides and has potential antibacterial activity against various Gram-positive bacteria. In the current study, the effect of pH and ionic strength (NaCl) on the conformational stability of plectasin variants has been investigated. At all physiochemical conditions, peptide secondary structures are intact throughout simulations. However, flexibility increases with pH because of the change in electrostatics around the distinct anionic tetrapeptide (9-12) stretch. Furthermore, plectasin interactions with NaCl were measured by determining the preferential interaction coefficients, Γ23. Generally, wild-type plectasin has higher preference for sodium ions as 9ASP is mutated in other variants. Overall, the Γ23 trend with pH for the two salt conditions remain the same for all variants predominately having accumulation of sodium ions around 10GLU and 12ASP. Insignificant changes in the overall peptide conformational stability are in agreement with the fact that plectasin has three cystines. Thermodynamic integration molecular dynamics simulations supplemented with nuclear magnetic resonance were employed to determine the degree of involvement of three different cystines to the overall structural integrity of the peptide. Both methods show the same order of cystine reduction and complete unfolding is observed only upon reduction of all cystines.

U2 - 10.1021/acs.jpcb.9b02370

DO - 10.1021/acs.jpcb.9b02370

M3 - Journal article

VL - 123

SP - 4867

EP - 4877

JO - Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical

JF - Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical

SN - 1520-6106

IS - 23

ER -

Indrakumar S, Zalar M, Pohl C, Nørgaard A, Streicher W, Harris P et al. Conformational Stability Study of a Therapeutic Peptide Plectasin Using Molecular Dynamics Simulations in Combination with NMR. Journal of Physical Chemistry Part B: Condensed Matter, Materials, Surfaces, Interfaces & Biophysical. 2019;123(23):4867-4877. https://doi.org/10.1021/acs.jpcb.9b02370

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