Distal Proton Shuttle Mechanism of Ribosome Catalysed Peptide Bond Formation—A Theoretical Study

Zhang, Xiaolin; Jiang, Yafei; Mao, Qiuyun; Tan, Hongwei; Li, Xichen; Chen, Guangju; Jia, Zongchao

doi:10.3390/molecules22040571

Cited by 6 publications

(13 citation statements)

References 28 publications

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“…Although the role of the 2′-OH group of A76 of peptidyl-tRNA is debatable, [33][34][35][36][37] we adopted a substrate-assisted catalysis model in which the 2′-OH group of A76 catalyzes peptide bond formation, 37) since this is consistent with experimental data and calculated models from previous mechanistic studies. 8,9,[12][13][14][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]33,34) The optimized geometries of TS1 and TS2 are shown in Fig. 3.…”

Section: Resultsmentioning

confidence: 99%

“…31) A similar zwitterionic species was characterized as a transient entity between the reactant complex and the transition state of peptide bond formation using QM/MM methods. 24,28) We tried to locate such a zwitterionic intermediate using ONIOM calculations and obtained an optimized geometry (Figs. 2 and 7, z-INT) when the C-N bond was frozen at 1.486 Å, which is the same length as the corresponding C-N bond in n-INT (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…18) Quantum chemical calculations have been used to study both stepwise and concerted mechanisms. [20][21][22][23][24][25][26][27][28][29][30][31] In one study of systems containing 44-56 atoms of the PTC analyzed using the M06-2X/6-311 + G(d,p) level of theory, C-N bond formation and C-O bond cleavage were accompanied by proton transfer of the NH 2 group, 2′-OH group of A76, and water molecules in the transition states (proton-shuttle mechanism); these authors showed that a stepwise reaction was favored over a concerted one and that the 2′-OH group of rRNA A2451 in the active site of the ribosome stabilized the transition states through hydrogen bonding. 22) In a previous study, we demonstrated the stepwise mechanism of the peptidyl transfer reaction in a ribosome system consisting of 2354 atoms using the ONIOM method 23) (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical Study of the Mechanism of Ribosomal Peptide Bond Formation Using the ONIOM Method

Fukushima

Esaki

2021

Chem. Pharm. Bull.

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Peptide bond formation in living cells occurs at the peptidyl transferase center (PTC) of the large ribosomal subunit and involves the transfer of the peptidyl group from peptidyl-tRNA to aminoacyl-tRNA. Despite numerous kinetic and theoretical studies, many details of this reaction -such as whether it proceeds via a stepwise or concerted mechanism-remain unclear. In this study, we calculated the geometry and energy of the transition states and intermediates in peptide bond formation in the PTC environment using the ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) method. The calculations indicated that the energy of the transition states of stepwise mechanisms are lower than those of concerted mechanisms and suggested that the reaction involves a neutral tetrahedral intermediate that is stabilized through the hydrogen-bonding network in the PTC environment. The results will lead to a better understanding of the mechanism of peptidyl transfer reaction, and resolve fundamental questions of the steps and molecular intermediates involved in peptide bond formation in the ribosome.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Theoretical Study of the Mechanism of Ribosomal Peptide Bond Formation Using the ONIOM Method

Fukushima

Esaki

2021

Chem. Pharm. Bull.

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“…5 Proton shuttle mechanisms characterized by distinct 8-and 6-membered rings have also been proposed. 5,[30][31][32] The inability of the PTC to adopt an induced-fit conformation with aminobenzoic acid monomers bound in the A site disrupts the water positions associated with the proton wire model. For instance, nucleotide A2602, which coordinates both W1 and W2 of the proton wire, is disordered and could not be modeled with high confidence.…”

Section: Relative Reactivity Of Aminobenzoic Acid Derivativesmentioning

confidence: 99%

Aminobenzoic acid derivatives obstruct induced fit in the catalytic center of the ribosome

Majumdar

Walker

Francis

et al. 2023

Preprint

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TheEscherichia coliribosome can incorporate a variety of non-L-α-amino acid monomers into polypeptide chains, but with poor efficiency. Although these monomers span a diverse set of compounds, there exists no high-resolution structural information regarding their positioning within the catalytic center of the ribosome, the peptidyl transferase center (PTC). Thus, details regarding the mechanism of amide bond formation and the structural basis for differences and defects in incorporation efficiency remain unknown. Within a set of three aminobenzoic acid derivatives—3-aminopyridine-4-carboxylic acid (Apy),ortho-aminobenzoic acid (oABZ), andmeta-aminobenzoic acid (mABZ)—the ribosome incorporates Apy into polypeptide chains with the highest efficiency, followed byoABZ and thenmABZ, a trend that does not track with the nucleophilicity of the reactive amines. Here, we report high resolution cryo-EM structures of the ribosome with these three aminobenzoic acid derivatives charged on tRNA bound in the aminoacyl-tRNA site (A site). These structures reveal how the aromatic ring of each monomer sterically blocks positioning of nucleotide U2506, thereby preventing rearrangement of nucleotide U2585 and the resulting induced fit in the PTC required for efficient amide bond formation. They also reveal disruptions to the "proton wire" responsible for facilitating formation and breakdown of the tetrahedral intermediate. Together, the cryo-EM structures reported here provide a clear rationale for differences in reactivity of aminobenzoic acid derivatives relative to L-α-amino acids and each other, and point to stereochemical constraints on the size and geometry of non-proteinogenic monomers that can be accepted efficiently by wild-type ribosomes.

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“…The mechanism of the peptidyl transferase reaction, called the "proton shuttle," is described in [50][51][52]. It has not yet been fully studied, but the main par-ticipants in the catalytic process have been identified.…”

Section: A a A Amentioning

confidence: 99%

On the Origin of Genetically Coded Protein Synthesis

Kovalenko¹

2021

Russ J Bioorg Chem

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How proteins with a specific amino acid sequence are synthesized in living organisms is no longer a mystery after the deciphering of the genetic code six decades ago. However, the origin of the system of genetically coded protein synthesis is still the subject of hypotheses that are only partially experimentally justified. Based on the review of works mainly of the last decade, the author formulated a hypothesis that largely concretizes certain stages of the formation of the translation system and the genetic code. The hypothesis is based on the concept of evolutionary reduction of the ambiguity of the primordial code. The distinctive positions of the hypothesis are as follows: (i) the emergence of aptamers, enriching the protocell by the rare catalytically active amino acids, and their evolutionary transformation into aaRS-like ribozymes which resulted in the operational code, (ii) simultaneous participation of a large number of amino acids (including noncanonical) in the formation of operational and genetic codes, (iii) the recognition of the whole codon of mRNA by the anticodon loop of proto-tRNA from the very beginning of coded protein synthesis, (iv) the coevolution of the operational and genetic codes that eliminated their initial ambiguity.

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Distal Proton Shuttle Mechanism of Ribosome Catalysed Peptide Bond Formation—A Theoretical Study

Cited by 6 publications

References 28 publications

Theoretical Study of the Mechanism of Ribosomal Peptide Bond Formation Using the ONIOM Method

Theoretical Study of the Mechanism of Ribosomal Peptide Bond Formation Using the ONIOM Method

Aminobenzoic acid derivatives obstruct induced fit in the catalytic center of the ribosome

On the Origin of Genetically Coded Protein Synthesis

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