Atomistic dynamics of a viral infection process: Release of membrane lytic peptides from a non-enveloped virus

Molecular simulations have played an instrumental role in uncovering the structural dynamics and physical properties of virus capsids. In this work, we move beyond equilibrium physicochemical characterization of a virus system to study a stage of the infection process that is required for viral proliferation. Despite many biochemical and functional studies, the molecular mechanism of host cell entry by non-enveloped viruses remains largely unresolved. Flock House virus (FHV) is a model system for non-enveloped viruses and is the subject of the current study. FHV infects through the acid-dependent endocytic pathway, where low pH triggers externalization of membrane-disrupting (γ) peptides from the capsid interior. Using all-atom equilibrium and enhanced sampling simulations, the mechanism and energetics of γ peptide liberation and the effect of pH on this process are investigated. Our computations agree with experimental findings and reveal nanoscopic details regarding the pH control mechanism, which are not readily accessible in experiments.

Atomistic Dynamics of a Viral Infection Process: Release of Membrane Lytic Peptides from a Non-Enveloped Virus

Molecular simulations have played an instrumental role in uncovering the structural dynamics and physical properties of virus capsids. In this work we move beyond equilibrium physicochemical characterization of a virus system to study a stage of the infection process which is required for viral proliferation. Despite many biochemical and functional studies, the molecular mechanism of host cell entry by non-enveloped viruses remains largely unresolved. Flock House Virus (FHV) is model system for non-enveloped viruses and is the subject of the current study. FHV infects through the acid-dependent endocytic pathway, where low pH triggers externalization of membrane disrupting (gamma) peptides from the capsid interior. Employing all-atom equilibrium and enhanced sampling simulations, the mechanism and energetics of gamma peptide liberation and the effect of pH on this process is investigated. Our computations agree with experimental findings and reveal nanoscopic details regarding the pH control mechanism which are not readily accessible in experiments.

MDA-MB-231 Breast Cancer Cells Resistant to Pleurocidin-Family Lytic Peptides Are Chemosensitive and Exhibit Reduced Tumor-Forming Capacity

Direct-acting anticancer (DAA) peptides are cytolytic peptides that show promise as novel anticancer agents. DAA peptides bind to anionic molecules that are abundant on cancer cells relative to normal healthy cells, which results in preferential killing of cancer cells. Due to the mechanism by which DAA peptides kill cancer cells, it was thought that resistance would be difficult to achieve. Here, we describe the generation and characterization of two MDA-MB-231 breast cancer cell-line variants with reduced susceptibility to pleurocidin-family and mastoparan DAA peptides. Peptide resistance correlated with deficiencies in peptide binding to cell-surface structures, suggesting that resistance was due to altered composition of the cell membrane. Peptide-resistant MDA-MB-231 cells were phenotypically distinct yet remained susceptible to chemotherapy. Surprisingly, neither of the peptide-resistant breast cancer cell lines was able to establish tumors in immune-deficient mice. Histological analysis and RNA sequencing suggested that tumorigenicity was impacted by alternations in angiogenesis and extracellular matrix composition in the peptide-resistant MDA-MB-231 variants. Collectively, these data further support the therapeutic potential of DAA peptides as adjunctive treatments for cancer.