Advances in Molecular Understanding of α-helical
Membrane-Active Peptides.

J 2021

Advances in Molecular Understanding of α-helical Membrane-Active Peptides.

KABELKA, Ivo and Robert VÁCHA

Basic information

Original name

Advances in Molecular Understanding of α-helical Membrane-Active Peptides.

Authors

KABELKA, Ivo (203 Czech Republic, belonging to the institution) and Robert VÁCHA (203 Czech Republic, guarantor, belonging to the institution)

Edition

Accounts of chemical research, American Chemical Society, 2021, 0001-4842

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 24.466

RIV identification code

RIV/00216224:14740/21:00118992

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1021/acs.accounts.1c00047

UT WoS

000648508400014

Keywords in English

ANTIMICROBIAL PEPTIDESPORE FORMATIONMAGAININ 2LIPID-BILAYERSBUFORIN IISIMULATIONSMECHANISMTRANSLOCATIONSPECTROSCOPYALAMETHICIN

Abstract

V originále

CONSPECTUS: Biological membranes separate the interior of cells or cellular compartments from their outer environments. This barrier function of membranes can be disrupted by membrane-active peptides, some of which can spontaneously penetrate through the membranes or open leaky transmembrane pores. However, the origin of their activity/toxicity is not sufficiently understood for the development of more potent peptides. To this day, there are no design rules that would be generally valid, and the role of individual amino acids tends to be sequence-specific. In this Account, we describe recent progress in understanding the design principles that govern the activity of membrane-active peptides. We focus on alpha-helical amphiphilic peptides and their ability to (1) translocate across phospholipid bilayers, (2) form transmembrane pores, or (3) act synergistically, i.e., to produce a significantly more potent effect in a mixture than the individual components. We refined the description of peptide translocation using computer simulations and demonstrated the effect of selected residues. Our simulations showed the necessity to explicitly include charged residues in the translocation description to correctly sample the membrane perturbations they can cause. Using this description, we calculated the translocation of helical peptides with and without the kink induced by the proline/glycine residue. The presence of the kink had no effect on the translocation barrier, but it decreased the peptide affinity to the membrane and reduced the peptide stability inside the membrane. Interestingly, the effects were mainly caused by the peptide's increased polarity, not the higher flexibility of the kink. Flexibility plays a crucial role in pore formation and affects distinct pore structures in different ways. The presence of a kink destabilizes barrel-stave pores, because the kink prevents the tight packing of peptides in the bundle, which is characteristic of the barrel-stave structure. In contrast, the kink facilitates the formation of toroidal pores, where the peptides are only loosely arranged and do not need to closely assemble. The exact position of the kink in the sequence further determines the preferred arrangement of peptides in the pore, i.e., an hourglass or U-shaped structure. In addition, we demonstrated that two self-associated (via termini) helical peptides could mimic the behavior of peptides with a helix-kink-helix motif. Finally, we review the recent findings on the peptide synergism of the archetypal mixture of Magainin 2 and PGLa peptides. We focused on a bacterial plasma membrane mimic that contains negatively charged lipids and lipids with negative intrinsic curvature. We showed that the synergistic action of peptides was highly dependent on the lipid composition. When the lipid composition and peptide/lipid ratios were changed, the systems exhibited more complex behavior than just the previously reported pore formation. We observed membrane adhesion, fusion, and even the formation of the sponge phase in this regime. Furthermore, enhanced adhesion/partitioning to the membrane was reported to be caused by lipid-induced peptide aggregation. In conclusion, the provided molecular insight into the complex behavior of membrane-active peptides provides clues for the design and modification of antimicrobial peptides or toxins.

Links

GA20-20152S, research and development project

Name: Proteinová přitažlivost a selektivita pro buněčné membrány

Investor: Czech Science Foundation

LL2007, research and development project

Name: Peptidoví zabijáci bakterií (Acronym: PeptideKillers)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

KABELKA, Ivo and Robert VÁCHA. Advances in Molecular Understanding of α-helical Membrane-Active Peptides. Accounts of chemical research. American Chemical Society, 2021, vol. 54, No 9, p. 2196-2204. ISSN 0001-4842. Available from: https://dx.doi.org/10.1021/acs.accounts.1c00047.

@article{1773100,
   author = {Kabelka, Ivo and Vácha, Robert},
   article_number = {9},
   doi = {http://dx.doi.org/10.1021/acs.accounts.1c00047},
   keywords = {ANTIMICROBIAL PEPTIDESPORE FORMATIONMAGAININ 2LIPID-BILAYERSBUFORIN IISIMULATIONSMECHANISMTRANSLOCATIONSPECTROSCOPYALAMETHICIN},
   language = {eng},
   issn = {0001-4842},
   journal = {Accounts of chemical research},
   title = {Advances in Molecular Understanding of α-helical Membrane-Active Peptides.},
   url = {https://pubs.acs.org/doi/10.1021/acs.accounts.1c00047},
   volume = {54},
   year = {2021}
}

TY  - JOUR
ID  - 1773100
AU  - Kabelka, Ivo - Vácha, Robert
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TI  - Advances in Molecular Understanding of α-helical Membrane-Active Peptides.
JF  - Accounts of chemical research
VL  - 54
IS  - 9
SP  - 2196-2204
EP  - 2196-2204
PB  - American Chemical Society
SN  - 00014842
KW  - ANTIMICROBIAL PEPTIDESPORE FORMATIONMAGAININ 2LIPID-BILAYERSBUFORIN IISIMULATIONSMECHANISMTRANSLOCATIONSPECTROSCOPYALAMETHICIN
UR  - https://pubs.acs.org/doi/10.1021/acs.accounts.1c00047
N2  - CONSPECTUS: Biological membranes separate the interior of cells or cellular compartments from their outer environments. This barrier function of membranes can be disrupted by membrane-active peptides, some of which can spontaneously penetrate through the membranes or open leaky transmembrane pores. However, the origin of their activity/toxicity is not sufficiently understood for the development of more potent peptides. To this day, there are no design rules that would be generally valid, and the role of individual amino acids tends to be sequence-specific. In this Account, we describe recent progress in understanding the design principles that govern the activity of membrane-active peptides. We focus on alpha-helical amphiphilic peptides and their ability to (1) translocate across phospholipid bilayers, (2) form transmembrane pores, or (3) act synergistically, i.e., to produce a significantly more potent effect in a mixture than the individual components. We refined the description of peptide translocation using computer simulations and demonstrated the effect of selected residues. Our simulations showed the necessity to explicitly include charged residues in the translocation description to correctly sample the membrane perturbations they can cause. Using this description, we calculated the translocation of helical peptides with and without the kink induced by the proline/glycine residue. The presence of the kink had no effect on the translocation barrier, but it decreased the peptide affinity to the membrane and reduced the peptide stability inside the membrane. Interestingly, the effects were mainly caused by the peptide's increased polarity, not the higher flexibility of the kink. Flexibility plays a crucial role in pore formation and affects distinct pore structures in different ways. The presence of a kink destabilizes barrel-stave pores, because the kink prevents the tight packing of peptides in the bundle, which is characteristic of the barrel-stave structure. In contrast, the kink facilitates the formation of toroidal pores, where the peptides are only loosely arranged and do not need to closely assemble. The exact position of the kink in the sequence further determines the preferred arrangement of peptides in the pore, i.e., an hourglass or U-shaped structure. In addition, we demonstrated that two self-associated (via termini) helical peptides could mimic the behavior of peptides with a helix-kink-helix motif. Finally, we review the recent findings on the peptide synergism of the archetypal mixture of Magainin 2 and PGLa peptides. We focused on a bacterial plasma membrane mimic that contains negatively charged lipids and lipids with negative intrinsic curvature. We showed that the synergistic action of peptides was highly dependent on the lipid composition. When the lipid composition and peptide/lipid ratios were changed, the systems exhibited more complex behavior than just the previously reported pore formation. We observed membrane adhesion, fusion, and even the formation of the sponge phase in this regime. Furthermore, enhanced adhesion/partitioning to the membrane was reported to be caused by lipid-induced peptide aggregation. In conclusion, the provided molecular insight into the complex behavior of membrane-active peptides provides clues for the design and modification of antimicrobial peptides or toxins.
ER  -

KABELKA, Ivo and Robert VÁCHA. Advances in Molecular Understanding of α-helical Membrane-Active Peptides. \textit{Accounts of chemical research}. American Chemical Society, 2021, vol.~54, No~9, p.~2196-2204. ISSN~0001-4842. Available from: https://dx.doi.org/10.1021/acs.accounts.1c00047.

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