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Updated: Jan 4, 2026
Fluorescent Leakage Assay to Investigate Membrane Destabilization by Cell-Penetrating Peptide
Published on: December 19, 2020
Molecular dynamics study of membrane permeabilization by wild-type and mutant lytic peptides from the non-enveloped
Shivangi Nangia1, Kevin J Boyd1, Eric R May1
1Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States of America.
Abstract:
Flock House virus (FHV) serves as a model system for understanding infection mechanisms utilized by non-enveloped viruses to transport across cellular membranes. During the infection cycle of FHV, a fundamental stage involves disruption of the endosomal membrane by membrane active peptides, following externalization of the peptides from the capsid interior. The FHV lytic agents are the 44 C-terminal amino acids residues of the capsid protein, which are auto-catalytically cleaved during the capsid maturation process. The cleaved peptides are termed γ peptides. In this study, we perform multi-scale molecular dynamics simulations including 40 μs all-atom molecular dynamics simulations to study the behavior of pre-inserted transmembrane lytic peptides at a high concentration in a neutral membrane. We study the dynamical organization among peptides to form oligomeric bundles in four systems including the wild-type γ peptide and three mutant forms; namely, a truncation mutant in which the 23 C-terminal residues are deleted (γ1), a construct where the 8 C-terminal residues of γ are fused to γ1 (Δ385-399 γ) and a single-point mutant (F402A γ), all of which have been experimentally shown to drastically affect infectivity and lytic activity compared to the wild-type γ. Our results shed light on the actions of varied forms of the FHV lytic peptide including membrane insertion, trans-membrane stability, peptide oligomerization, water permeation activity and dynamic pore formation. Findings from this study provide detailed structural information and rationale for the differences in lytic activity among variants of FHV γ.
Insights
Flock House virus (FHV) lytic peptides disrupt cell membranes. Molecular dynamics simulations reveal how wild-type and mutant FHV γ peptides form bundles, create pores, and affect membrane stability, explaining differences in viral infectivity.
Area of Science:
- Virology
- Biophysics
- Structural Biology
Background:
- Flock House virus (FHV) is a model for non-enveloped virus infection.
- FHV infection involves membrane disruption by lytic peptides released from the capsid.
- These FHV γ peptides are crucial for viral entry and infectivity.
Purpose of the Study:
- To investigate the behavior of FHV γ peptides in neutral membranes using molecular dynamics simulations.
- To analyze the self-assembly and pore-forming capabilities of wild-type and mutant FHV γ peptides.
- To elucidate the structural basis for varying lytic activities among FHV γ peptide variants.
Main Methods:
- Utilized multi-scale molecular dynamics simulations, including 40 μs of all-atom simulations.
- Studied wild-type FHV γ peptide and three mutants (γ1, Δ385-399 γ, F402A γ) at high concentration in a neutral membrane.
- Analyzed peptide insertion, transmembrane stability, oligomerization, water permeation, and pore formation.
Main Results:
- Observed dynamical organization of FHV γ peptides into oligomeric bundles within the membrane.
- Characterized membrane insertion, stability, and water permeation activities of different peptide variants.
- Identified distinct behaviors in pore formation dynamics among wild-type and mutant peptides.
- Provided structural insights into how mutations affect peptide aggregation and lytic function.
Conclusions:
- FHV γ peptide variants exhibit differential membrane interactions and pore-forming activities.
- Structural dynamics of peptide oligomerization correlate with observed lytic activity and infectivity.
- This study offers a detailed molecular understanding of FHV infection mechanisms at the membrane interface.
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