Escapement mechanisms: Efficient free energy transduction by reciprocally‐coupled gating

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2020-05, Vol.88 (5), p.710-717
• Main Author: Carter, Charles W.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; allosteric control; Allosteric Regulation; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Binding Sites; Biocatalysis; Biomechanical Phenomena; Catalysis; Catalytic Domain; Cations, Divalent; combinatorial mutagenesis; Computer applications; Coupling (molecular); Domains; energetic coupling; Energy transduction; far from equilibrium; Free energy; free energy surfaces; Gating; Geobacillus stearothermophilus - chemistry; Geobacillus stearothermophilus - enzymology; Geobacillus stearothermophilus - genetics; Hydrolysis; Kinetics; Magnesium; Magnesium - chemistry; Magnesium - metabolism; Models, Molecular; Molecular modelling; NTP hydrolysis; Pendulums; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Signal Transduction; Substrate Specificity; Thermodynamics; transducing enzymes; tRNA Trp; Tryptophan; Tryptophan - chemistry; Tryptophan - metabolism; Tryptophan-tRNA Ligase - chemistry; Tryptophan-tRNA Ligase - genetics; Tryptophan-tRNA Ligase - metabolism
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.25856

Conversion of the free energy of NTP hydrolysis efficiently into mechanical work and/or information by transducing enzymes sustains living systems far from equilibrium, and so has been of interest for many decades. Detailed molecular mechanisms, however, remain puzzling and incomplete. We previously reported that catalysis of tryptophan activation by tryptophanyl‐tRNA synthetase, TrpRS, requires relative domain motion to re‐position the catalytic Mg2+ ion, noting the analogy between that conditional hydrolysis of ATP and the escapement mechanism of a mechanical clock. The escapement allows the time‐keeping mechanism to advance discretely, one gear at a time, if and only if the pendulum swings, thereby converting energy from the weight driving the pendulum into rotation of the hands. Coupling of catalysis to domain motion, however, mimics only half of the escapement mechanism, suggesting that domain motion may also be reciprocally coupled to catalysis, completing the escapement metaphor. Computational studies of the free energy surface restraining the domain motion later confirmed that reciprocal coupling: the catalytic domain motion is thermodynamically unfavorable unless the PPi product is released from the active site. These two conditional phenomena—demonstrated together only for the TrpRS mechanism—function as reciprocally‐coupled gates. As we and others have noted, such an escapement mechanism is essential to the efficient transduction of NTP hydrolysis free energy into other useful forms of mechanical or chemical work and/or information. Some implementation of both gating mechanisms—catalysis by domain motion and domain motion by catalysis—will thus likely be found in many other systems.