Stability of β-turn in LaR2C-N7 peptide for its translation-inhibitory activity against hepatitis C viral infection: A molecular dynamics study

Hepatitis C virus (HCV) requires an essential host factor, human La protein, for its translation and replication activity. Earlier, it was demonstrated that a 24-mer synthetic peptide (LaR2C) encompassing residues 112 to 184 of the natural human La protein interacts with the HCV internal ribosome entry site (IRES) and inhibits translation. Interestingly, a shorter version of the same LaR2C peptide, LaR2C-N7, containing residues 174 to 180 (KYKETDL), with a unique β-turn secondary structure, is sufficient to inhibit IRES mediated translation of HCV. Hence, it is imperative to understand the role of each amino acid of this heptapeptide towards β-turn formation which will then help in designing potential drugs against HCV infection. Here, we use Nanoscale Molecular Dynamics (NAMD) simulation to investigate the factors modulating its β-turn formation and stability. Using 100 ns simulation paradigms, we find that the peptide populated the type 1 β-turn conformation in its free form in solution. However, simulation of the single-site mutants of the heptapeptide revealed that none of the 7 mutants retained the β-turn conformation with sufficient stability. We observed that the β-turn was stabilized mainly by the side chain interaction, salt-bridge and weak hydrogen bonds between K3 and D6 residues. Y2, K1 and K3 sites upon mutation heavily destabilized the β-turn when compared to alteration at the E4 and T5 sites which would then drastically reduce its HCV RNA IRES binding capabilities. Taken together, our results provide a basis for designing peptidomimetics as potential anti-HCV drug candidates.