1. The ribosome 204

2. Peptide bond formation is catalyzed by RNA 205

3. Characteristics of the uncatalyzed reaction 207

4. Potential catalytic strategies of the ribosome 207

5. Experimental systems 208

6. Substrate binding in the PT center 210

7. Induced fit in the active site 211

8. pH dependence of peptide bond formation 212

9. Reaction with full-length aa-tRNA 214

10. Role of active-site residues 215

11. pH-dependent structural changes of the active site 216

12. Entropic catalysis 217

13. Role of 2′-OH of A76 in P-site tRNA 218

14. Catalysis by proton shuttling 219

15. Plasticity of the active site 220

16. Conclusions 221

17. Acknowledgments 222

18. References 222

Peptide bond formation is the fundamental reaction of ribosomal protein synthesis. The ribosome's active site – the peptidyl transferase center – is composed of rRNA, and thus the ribosome is the largest known RNA catalyst. The ribosome accelerates peptide bond formation by 107-fold relative to the uncatalyzed reaction. Recent progress of structural, biochemical and computational approaches has provided a fairly detailed picture of the catalytic mechanisms employed by the ribosome. Energetically, catalysis is entirely entropic, indicating an important role of solvent reorganization, substrate positioning, and/or orientation of the reacting groups within the active site. The ribosome provides a pre-organized network of electrostatic interactions that stabilize the transition state and facilitate proton shuttling involving ribose hydroxyl groups of tRNA. The catalytic mechanism employed by the ribosome suggests how ancient RNA-world enzymes may have functioned.