Computational outlook on the ribosome as an entropy trap

Monajemi, Hadieh; Zain, Sharifuddin M.; Abdullah, Wan Ahmad Tajuddin Wan

doi:10.1016/j.comptc.2011.08.017

Cited by 6 publications

(5 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The proposed neutral stepwise mechanism (Figure 2C) is also similar to previously suggested transition states for peptide bond formation in which the carbonyl oxygen of the P-site substrate is protonated by the P-site 2′-OH group. 15,16 However, it should be noted that the highest resolution crystal structures of the PTC with nonreactive substrate analogues do not support such a proton transfer due to an unfavorable geometry. 17−19 The key steps in the neutral mechanism 14 are the formation and collapse of a neutral tetrahedral intermediate, which both occur through a concerted proton transfer (Figure 2C).…”

Section: ■ Introductionmentioning

confidence: 99%

Peptide Release on the Ribosome Involves Substrate-Assisted Base Catalysis

2016

View full text Add to dashboard Cite

Termination of protein synthesis on the ribosome involves hydrolysis of the ester bond between the P-site tRNA and the nascent peptide chain. This reaction occurs in the peptidyl transferase center and is triggered by the class I release factors RF1 and RF2 in prokaryotes. Peptidyl-tRNA hydrolysis is pH-dependent, and experimental results suggest that an ionizable group with pK a > 9 is involved in the reaction. The nature of this group is, however, unknown. To resolve this problem, we conducted density functional theory calculations using a large cluster model of the peptidyl transferase center. Our calculations reveal that peptidyl-tRNA hydrolysis occurs via a base-catalyzed mechanism with a predicted activation energy of 15.8 kcal mol −1 , which is in good agreement with experimental data. In this mechanism, the P-site A76 2′-OH group is deprotonated and acts as the general base by activating the nucleophilic water molecule. The energy cost of deprotonating the 2′-hydroxyl group at pH 7.5 is estimated to be about 8 kcal mol −1 , on the basis of its experimental pK a in aqueous solution, and this step is predicted to be the source of the observed pH dependence. The proposed mechanism is consistent not only with experimentally derived activation energies but also with the observed kinetic solvent isotope effect.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Peptide Release on the Ribosome Involves Substrate-Assisted Base Catalysis

2016

View full text Add to dashboard Cite

show abstract

“…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%

“…[10][11][12][13] However, there is also evidence for a concerted mechanism. [14][15][16][17][18][19] In a PTC model system comprising 76 atoms, calculated based on the B3LYP/6-311G** level of theory, C-N bond formation and C-O bond cleavage in the transition state occurred simultaneously with proton transfer in a cyclic hydrogen-bonding system that included the ester C=O group, NH 2 group, and 2′-OH group of A76; furthermore, the water molecule trapped at the PTC participated in the hydrogen-bonding network and reduced the activation energy of peptide bond formation. 19) The latter was supported by QM/MM free energy simulations.…”

Section: Introductionmentioning

confidence: 99%

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

Fukushima

Esaki

2021

Chem. Pharm. Bull.

View full text Add to dashboard Cite

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.

show abstract

“…[60] This rotary-like motion is expected to be facilitated by the approximate 2-fold symmetry of the PTC, and QM calculations showed that rotation-like pathways can be associated with lower barriers than those calculated for alternate paths. [84,85] The approximate two-fold symmetry of the PTC has inspired the idea that the PTC may be a relic from an ancestral protoribosome dimer that was first competent for peptide bond formation. [86,87] To explore the feasibility of this notion, a pairwise interaction scheme, called kernel energy method (KEM) [88,89] was applied over the hypothesized dimeric protoribosome system, which predicted that PTC-like RNA dimers could adopt stable configurations and bind substrates that are chemically similar to amino acids.…”

Section: Dynamics Of Chemical Reactionsmentioning

confidence: 99%

“…[ 60 ] This rotary‐like motion is expected to be facilitated by the approximate 2‐fold symmetry of the PTC, and QM calculations showed that rotation‐like pathways can be associated with lower barriers than those calculated for alternate paths. [ 84,85 ]…”

Section: Dynamics Of Chemical Reactionsmentioning

confidence: 99%

The energy landscape of the ribosome

Byju,

Hassan,

Whitford

2023

Biopolymers

View full text Add to dashboard Cite

The ribosome is a prototypical assembly that can be used to establish general principles and techniques for the study of biological molecular machines. Motivated by the fact that the dynamics of every biomolecule is governed by an underlying energy landscape, there has been great interest to understand and quantify ribosome energetics. In the present review, we will focus on theoretical and computational strategies for probing the interactions that shape the energy landscape of the ribosome, with an emphasis on more recent studies of the elongation cycle. These efforts include the application of quantum mechanical methods for describing chemical kinetics, as well as classical descriptions to characterize slower (microsecond to millisecond) large‐scale (10–100 Å) rearrangements, where motion is described in terms of diffusion across an energy landscape. Together, these studies provide broad insights into the factors that control a diverse range of dynamical processes in this assembly.

show abstract

Computational outlook on the ribosome as an entropy trap

Cited by 6 publications

References 18 publications

Peptide Release on the Ribosome Involves Substrate-Assisted Base Catalysis

Peptide Release on the Ribosome Involves Substrate-Assisted Base Catalysis

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

The energy landscape of the ribosome

Contact Info

Product

Resources

About