Simulation study of the ability of a computationally-designed peptide to recognize target tRNALys3 and other decoy tRNAs

In this paper, we investigate the ability of our computationally-designed peptide, Pept10 (PNWNGNRWLNNCLRG), to recognize the anticodon stem and loop (ASL) domain of the hypermodified tRNALys3 (mcm5s2U34,ms2t6A37), a reverse transcription primer of HIV replication. Five other ASLs, the singly modified ASLLys3(ms2t6A37), ASLLys3(s2U34), ASLLys3(Ψ39), ASLLys1,2(t6A37), and ASLGlu(s2U34), were used as decoys. Explicit-solvent atomistic molecular dynamics simulations were performed to examine the process of binding of Pept10 with the target ASLLys3(mcm5s2U34,ms2t6A37) and the decoy ASLs. Simulation results demonstrated that Pept10 is capable of recognizing the target ASLLys3(mcm5s2U34,ms2t6A37) as well as one of the decoys, ASLLys3(Ψ39), but screens out the other four decoy ASLs. The interchain van der Waals (VDW) and charge–charge (ELE + EGB) energies for the two best complexes were evaluated to shed light on the molecular recognition mechanism between Pept10 and ASLs. The results indicated that Pept10 recognizes and binds to the target ASLLys3 (mcm5s2U34,ms2t6A37) through residues W3 and R7 which interact with the nucleotides mcm5s2U34, U35, and ms2t6A37 via the interchain VDW energy. Pept10 also recognizes the decoy ASLLys3(Ψ39) through residue R14 which contacts the nucleotide U36 via the interchain VDW energy. Regardless of the type of ASL, the positively charged arginines on Pept10 are attracted to the negatively charged phosphate linkages on the ASL via the interchain ELE + EGB energy, thereby enhancing the binding affinity.