Simulation study of the ability of a computationally-designed peptide to recognize target tRNA^Lys3 and other decoy...

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 tRNA^Lys3 (mcm⁵ s² U₃₄ ,ms² t⁶ A₃₇ ), a reverse transcription primer of HIV replication. Five other ASLs, the singly modified ASL^Lys3 (ms² t⁶ A₃₇ ), ASL^Lys3 (s² U₃₄ ), ASL^Lys3 (Ψ₃₉ ), ASL^Lys1,2 (t⁶ A₃₇ ), and ASL^Glu (s² U₃₄ ), were used as decoys. Explicit-solvent atomistic molecular dynamics simulations were performed to examine the process of binding of Pept10 with the target ASL^Lys3 (mcm⁵ s² U₃₄ ,ms² t⁶ A₃₇ ) and the decoy ASLs. Simulation results demonstrated that Pept10 is capable of recognizing the target ASL^Lys3 (mcm⁵ s² U₃₄ ,ms² t⁶ A₃₇ ) as well as one of the decoys, ASL^Lys3 (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 ASL^Lys3 (mcm⁵ s² U₃₄ ,ms² t⁶ A₃₇ ) through residues W₃ and R₇ which interact with the nucleotides mcm⁵ s² U₃₄ , U₃₅ , and ms² t⁶ A₃₇ via the interchain VDW energy. Pept10 also recognizes the decoy ASL^Lys3 (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.