Molecular dynamics study of membrane permeabilization by wild-type and mutant lytic peptides from the non-enveloped Flock House virus

• Published in: Biochimica et biophysica acta. Biomembranes Vol. 1862; no. 2; p. 183102
• Main Authors: Nangia, Shivangi, Boyd, Kevin J., May, Eric R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2020
• Subjects: Cell Membrane - chemistry; Cell Membrane - drug effects; Membrane active peptides; Membrane peptide interactions; Membrane pores; Molecular Dynamics Simulation; Molecular dynamics simulations; Multiscale modeling; Mutation; Nodaviridae - chemistry; Non-enveloped viruses; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - pharmacology; Protein Binding; Protein Multimerization; Viral Proteins - chemistry; Non-enveloped viruses; Molecular dynamics simulations; Membrane pores; Membrane active peptides; Membrane peptide interactions; Multiscale modeling
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2019.183102

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. [Display omitted] •C-terminus of the FHV lytic peptide is critical for efficient membrane disruption.•Mutant lytic peptides lacking C-terminus display low water permeation in membrane.•Higher order oligomerization occurs for only C-terminus containing lytic peptides.•Highly dynamical clustering of lytic peptides and water pores is observed.•FHV lytic peptides show characteristics similar to anti-microbial peptides.