Amino Acid Signature Enables Proteins to Recognize Modified tRNA

Spears, Jessica L.; Xiao, Xingqing; Hall, Carol K.; Agris, Paul F.

doi:10.1021/bi401174h

Cited by 28 publications

(35 citation statements)

References 44 publications

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“…The non-polar solvation energy G GBSUR is calculated by multiplying the solvent-accessible surface area of the solute molecules by the surface tension (in this work, the surface tension is set to 0.0072 kcal/mol/Å 2 ). More details concerning the calculation of each energy term can be found in our previous work [22, 29]. It is worth noting that the internal energy Δ U INT is always zero in the calculation of the binding free energy since U INT is associated with the individual internal motions of ligand and receptor, and this term does not refer to the binding between ligand and receptor.…”

Section: Structures and Methodsmentioning

confidence: 99%

“…ASL Lys3 , with the ultimate purpose of breaking the replication cycle of human immunodeficiency virus-1. This search algorithm has been validated experimentally by synthesizing and testing peptide sequences selected in this manner against ASL Lys3 [22]. …”

Section: Introductionmentioning

confidence: 99%

“…This search algorithm has been validated experimentally by synthesizing and testing peptide sequences selected in this manner against ASL Lys3 . [22] In this article, we describe a major improvement to our peptide design algorithm and use it to generate a library of peptides predicted to bind boxB RNA with affinities greater than the wild-type k N(2-22) peptide. The major improvement is the addition of an energy minimization step to the search algorithm that can move the amino acid sidechains in a broad conformational space during peptide sequence evolution.…”

Section: Introductionmentioning

confidence: 99%

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Adding energy minimization strategy to peptide‐design algorithm enables better search for RNA‐binding peptides: Redesigned λ N peptide binds boxB RNA

et al. 2016

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Our previously-developed peptide-design algorithm was improved by adding an energy minimization strategy which allows the amino acid sidechains to move in a broad configuration space during sequence evolution. In this work, the new algorithm was used to generate a library of 21-mer peptides which could substitute for λ N peptide in binding to boxB RNA. Six potential peptides were obtained from the algorithm, all of which exhibited good binding capability with boxB RNA. Atomistic molecular dynamics simulations were then conducted to examine the ability of the λ N peptide and three best evolved peptides, viz. Pept01, Pept26 and Pept28, to bind to boxB RNA. Simulation results demonstrated that our evolved peptides are better at binding to boxB RNA than the λ N peptide. Sequence searches using the old (without energy minimization strategy) and new (with energy minimization strategy) algorithms confirm that the new algorithm is more effective at finding good RNA-binding peptides than the old algorithm.

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Section: Structures and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adding energy minimization strategy to peptide‐design algorithm enables better search for RNA‐binding peptides: Redesigned λ N peptide binds boxB RNA

et al. 2016

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“…74,75 A 15-amino acid signature peptide derived from NCp7 (R-W-Q/N-H-X 2 -F-Pho-X-G/A-W-R-X 2 -G, where X D any amino acids and Pho D hydrophobic) specifically recognizes modified htRNA Lys3(UUU) with a binding affinity 10-fold higher than that of a random sequence. 76 Thus, modifications of htRNA Lys3(UUU) stabilize the native structure of the anticodon loop and provide a recognition element that is utilized both in normal translation and non-canonical tRNA functions.…”

Section: Human Trnamentioning

confidence: 99%

tRNA wobble modifications and protein homeostasis

Ranjan

Rodnina

2016

Translation

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ABSTRACTtRNA is a central component of the protein synthesis machinery in the cell. In living cells, tRNAs undergo numerous post-transcriptional modifications. In particular, modifications at the anticodon loop play an important role in ensuring efficient protein synthesis, maintaining protein homeostasis, and helping cell adaptation and survival. Hypo-modification of the wobble position of the tRNA anticodon loop is of particular relevance for translation regulation and is implicated in various human diseases. In this review we summarize recent evidence of how methyl and thiol modifications in eukaryotic tRNA at position 34 affect cellular fitness and modulate regulatory circuits at normal conditions and under stress.

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“…This suggests the possibility of interfering with or even stopping HIV reverse transcription by blocking the recruitment of the specific primer

{tRNA}_{UUU}^{Lys 3}

by the HIV . Toward this aim, one of us (Agris) has been using peptide phage display libraries to identify short peptide chains that could mimic the ability of the viral nucleocapsid protein to bind selectively to the

{tRNA}_{UUU .}^{Lys 3}

One 15‐mer peptide called P6 (sequence: RVTHHAFLGAHRTVG ) was found in vitro to have a relatively good binding capability to the tRNA Lys3 and to mimic functions of the virus' nucleocapsid protein . Since synthesis and testing of all possible peptide sequences is not practical, we have devised a computational protein‐design algorithm to seek other good peptide candidates in a fast and effective manner.…”

Section: Introductionmentioning

confidence: 99%

Introducing folding stability into the score function for computational design of RNA‐binding peptides boosts the probability of success

2016

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A computational strategy that integrates our peptide search algorithm with atomistic molecular dynamics simulation was used to design rational peptide drugs that recognize and bind to the anticodon stem and loop domain (ASL(Lys3)) of human tRNAUUULys3 for the purpose of interrupting HIV replication. The score function of the search algorithm was improved by adding a peptide stability term weighted by an adjustable factor λ to the peptide binding free energy. The five best peptide sequences associated with five different values of λ were determined using the search algorithm and then input in atomistic simulations to examine the stability of the peptides' folded conformations and their ability to bind to ASL(Lys3). Simulation results demonstrated that setting an intermediate value of λ achieves a good balance between optimizing the peptide's binding ability and stabilizing its folded conformation during the sequence evolution process, and hence leads to optimal binding to the target ASL(Lys3). Thus, addition of a peptide stability term significantly improves the success rate for our peptide design search.

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Amino Acid Signature Enables Proteins to Recognize Modified tRNA

Cited by 28 publications

References 44 publications

Adding energy minimization strategy to peptide‐design algorithm enables better search for RNA‐binding peptides: Redesigned λ N peptide binds boxB RNA

Adding energy minimization strategy to peptide‐design algorithm enables better search for RNA‐binding peptides: Redesigned λ N peptide binds boxB RNA

tRNA wobble modifications and protein homeostasis

Introducing folding stability into the score function for computational design of RNA‐binding peptides boosts the probability of success

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