Ribonucleic acid (RNA) is an essential biomolecule for encoding and transmitting genetic information in RNA viruses, including Ebola, Influenza, HIV, and SARS-CoV-2. The highly conserved non-coding RNA (ncRNA) elements in viral genomes fold into complex three-dimensional structures to regulate the viral life cycle through their molecular interaction with RNA binding proteins. Therefore, these protein-RNA interfaces have become key targets for developing novel therapeutic approaches. Here, we probe the physical interactions between a highly conserved viral RNA element from the HIV-1 genome by two helical peptides, a native (Rev) peptide and a lab-evolved (RSG1.2) peptide. Specifically, we investigated the physical interactions between the viral RNA molecule and helical peptides by computing free energy changes on mutating key amino-acid residues involved in the recognition of an internal loop in the viral RNA molecule. Our results reveal unique interaction patterns in residues underlying a higher binding specificity and affinity of the lab-evolved peptide in comparison to the native peptide. Specifically, we discovered that the native peptide employs base-specific hydrogen bonding, sugar-phosphate backbone interactions, and cation-pi interactions for the recognition of the viral RNA molecule. In contrast, the lab-evolved peptide binds to the viral RNA via base-specific contacts, using hydrophobic and cation-pi contacts, and is held in place by an intrapeptide salt-bridge network to form sugar-phosphate interactions.

Peptide Recognition by Viral RNA

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ACS Fall 2022

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