Abstract
In this work, we have investigated a novel distal proton shuttle mechanism of ribosome catalyzed peptide bond formation reaction. The reaction was found to follow a two-step mechanism. A distal water molecule located about 6.1 Å away from the attacking amine plays as a proton acceptor and results in a charge-separated intermediate that is stabilized by the N terminus of L27 and the A-site A76 5′-phosphate. The ribose A2451 bridges the proton shuttle pathway, thus plays critical role in the reaction. The calculated 27.64 kcal·mol−1 free energy barrier of the distal proton shuttle mechanism is lower than that of eight-membered ring transition state. The distal proton shuttle mechanism studied in this work can provide new insights into the important biological peptide synthesis process.
Highlights
Ribosomes are responsible for the translation process of the genetic central dogma
We performed a DFT study on the peptide bond formation reaction catalyzed by the ribosome
The calculated energy barrier of the rate-limiting step of the distal proton shuttle pathway is more favorable than the canonical eight-membered ring mechanism and agrees well with that determined from kinetic experiments
Summary
The peptide bond formation reaction catalyzed by ribosomes enables essential protein synthesis for all living organisms [1]. Peptide bond formation reaction proceeds with the aminoacyl-transfer RNA (tRNA, bound to the A site of ribosome) nucleophilic attacking on ester carbon of the peptidyl-tRNA (bound to the P site), accompanied by a proton transfer from α-amino group of aminoacyl-tRNA to deacylated 30 hydroxyl. A six-membered ring transition state during peptide formation (shown in Scheme 1a) was proposed based on the X-ray structure of the large ribosomal subunit complexed with transition state analogue (TSA), in which the 20 hydroxyl of A76 in the P site acts as a general base to abstract the proton from the α-amino group and donates another proton to the deacylated 30 hydroxyl to complete the reaction [2].
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