Abstract
The conserved and structured elements in viral RNA genomes interact with proteins to regulate various events in the viral life cycle and have become key targets for developing novel therapeutic approaches. We probe physical interactions between lab-evolved proteins and a viral RNA element from the HIV-1 genome. Specifically, we study the role of an arginine-rich loop in recognition of designed proteins by the viral RNA element. We report free energy calculations to quantitatively estimate the protein/RNA binding energetics, focusing on the mutations of arginine residues involved in recognition of the major groove of RNA by proteins.
Highlights
RNA viruses, including influenza, Ebola, HIV, and SARS-CoV-2, are among the most efficient and compact carriers of biological information in nature,[1] and are implicated in many ongoing and emerging threats to human health.[2,3,4,5] The highly compact and short genomes of these viruses provide a limited number of protein targets for anti-viral therapeutics because of the lack of well-defined binding pockets.[6]
While conventional molecular dynamics (MD) simulations suggest that Arg[47], Arg[49], and Arg[52] (Arg[50] in case of P1) in the b2–b3 loop of TAR binding protein (TBP) participate in recognition of the major groove of trans-activation response element RNA (TAR), they do not quantify the binding contributions of these residues
Our results show that this energetic difference in the R49A mutation is due to saltbridging interactions between the side-chain of Arg[49] (P3) and TAR nucleotides compared to hydrogen bonding of Arg[49] with the Hoogsteen edge of GUA28 in P2
Summary
RNA viruses, including influenza, Ebola, HIV, and SARS-CoV-2, are among the most efficient and compact carriers of biological information in nature,[1] and are implicated in many ongoing and emerging threats to human health.[2,3,4,5] The highly compact and short genomes of these viruses provide a limited number of protein targets for anti-viral therapeutics because of the lack of well-defined binding pockets.[6]. RNA–protein interactions often span a large surface area, which makes it difficult to target them with small molecules.[12,13,14,15,16,17] By virtue of their size, peptides can often bind to RNA with excellent potency and may modulate the biological function.[18,19] Many RNA binding proteins exploit arginine-rich b-hairpin structures to recognize RNA molecules.[20,21] b-hairpin peptides are of particular interest for targeting viral RNA molecules. Small b-hairpin peptides that potently and selectively recognize viral RNA molecules are rare and de novo design of these molecules is an unresolved challenge,[22,23] advances in protein engineering have facilitated the design and screening of lab-evolved RNA binding peptides
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