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Role of salt-bridging interactions in recognition of viral RNA by arginine-rich peptides.

ABSTRACT: Interactions between RNA molecules and proteins are critical to many cellular processes and are implicated in various diseases. The RNA-peptide complexes are good model systems to probe the recognition mechanism of RNA by proteins. In this work, we report studies on the binding-unbinding process of a helical peptide from a viral RNA element using nonequilibrium molecular dynamics simulations. We explored the existence of various dissociation pathways with distinct free-energy profiles that reveal metastable states and distinct barriers to peptide dissociation. We also report the free-energy differences for each of the four pathways to be 96.47 ± 12.63, 96.1 ± 10.95, 91.83 ± 9.81, and 92 ± 11.32 kcal/mol. Based on the free-energy analysis, we further propose the preferred pathway and the mechanism of peptide dissociation. The preferred pathway is characterized by the formation of sequential hydrogen-bonding and salt-bridging interactions between several key arginine amino acids and the viral RNA nucleotides. Specifically, we identified one arginine amino acid (R8) of the peptide to play a significant role in the recognition mechanism of the peptide by the viral RNA molecule.

SUBMITTER: Levintov L

PROVIDER: S-EPMC8633718 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Role of salt-bridging interactions in recognition of viral RNA by arginine-rich peptides.

Levintov Lev L Vashisth Harish H

Biophysical journal 20211026 22

Interactions between RNA molecules and proteins are critical to many cellular processes and are implicated in various diseases. The RNA-peptide complexes are good model systems to probe the recognition mechanism of RNA by proteins. In this work, we report studies on the binding-unbinding process of a helical peptide from a viral RNA element using nonequilibrium molecular dynamics simulations. We explored the existence of various dissociation pathways with distinct free-energy profiles that revea ...[more]

PMID: 34710377

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Project description:The self-assembly behavior and antimicrobial activity of two designed amphiphilic peptides, R3F3 and R4F4, containing short hydrophobic phenylalanine (F) and cationic arginine (R) sequences, are investigated. The conformation of the peptides was examined using circular dichroism and FTIR spectroscopy, which show that they have a disordered secondary structure. Concentration-dependent fluorescence assays show the presence of a critical aggregation concentration (cac) for each peptide. Above the cac, small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) reveal a population of twisted tapes for R3F3 and nanosheets for R4F4. The interaction of the peptides with model bacterial membranes comprising mixtures of the lipids DPPG [1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol] and DPPE [1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine], was studied using SAXS and cryogenic-TEM. Analysis of the SAXS structure factor indicates that R3F3 interacts with lipid bilayers by inducing correlation between bilayers, whereas R4F4 interacts with the bilayers causing an increase in polydispersity of the vesicle wall thickness. Both peptides break vesicles with a 1:3 DPPG:DPPE composition, which is close to the ratio of PG and PE lipids observed in the lipid membrane of Pseudomonas aeruginosa, a pathogen responsible for serious infections and which has developed antimicrobial resistant strains. Both peptides show activity against this bacterium in planktonic form. Peptide R4F4 shows particularly strong bioactivity against this microbe, with a minimum inhibitory concentration (MIC) value in the range of concentrations where the peptide is cytocompatible. It was further shown to have activity against other Pseudomonas species including the common plant pathogen Pseudomonas syringae. Finally, we show that R4F4 inhibits the development of P. aeruginosa biofilms. This was examined in detail and a proposed mechanism involving binding of the signaling molecule c-di-GMP is suggested, based on circular dichroism spectroscopy studies and Congo red assays of extracellular polysaccharides produced by the stressed bacteria. Thus, R4F4 is a promising candidate antimicrobial peptide with activity against Pseudomonas species.

Dataset Information

Role of salt-bridging interactions in recognition of viral RNA by arginine-rich peptides.

Publications

Role of salt-bridging interactions in recognition of viral RNA by arginine-rich peptides.

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