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Comparing the Affinity of GTPase-binding Proteins using Competition Assays
Published on: October 8, 2015
Conformational selection by the aIF2 GTPase: a molecular dynamics study of functional pathways
Priyadarshi Satpati1, Thomas Simonson
1Laboratoire de Biochimie (CNRS UMR7654), Department of Biology, Ecole Polytechnique, 91128 Palaiseau, France.
Biochemistry
|December 15, 2011
Summary
Archaeal initiation factor 2 (aIF2), a GTPase crucial for protein synthesis, undergoes conformational changes. Research suggests a "MIXED" state may be a functional intermediate in its GTP hydrolysis cycle.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Archaeal initiation factor 2 (aIF2) is a GTPase essential for initiating protein biosynthesis.
- It cycles between a GTP-bound
- ON
- state (tRNA binding) and a GDP-bound
- OFF
- state (tRNA release).
- Understanding the conformational transitions after GTP hydrolysis is key to its function.
Purpose of the Study:
- To investigate the conformational states and transitions of aIF2 following GTP hydrolysis.
- To determine the energetic feasibility of different pathways from the ON:GDP:P(i) state to the OFF:GDP product.
- To explore the potential role of a newly identified
- MIXED
- conformation.
Main Methods:
- Molecular dynamics simulations were employed to calculate free energy changes.
- Free energy of inorganic phosphate (P(i)) dissociation was computed for different states.
- Thermodynamic estimations were used to assess the stability of intermediate states.
Main Results:
- P(i) dissociation from the ON state is highly favorable.
- Transition to the OFF state before P(i) dissociation is energetically uphill or weakly downhill.
- P(i) dissociation from the proposed MIXED conformation is weakly unfavorable, suggesting its potential as a functional intermediate.
Conclusions:
- The study elucidates potential pathways for aIF2 conformational changes post-GTP hydrolysis.
- The MIXED conformation is proposed as a potentially stable and functional intermediate in the aIF2 cycle.
- These findings enhance understanding of the aIF2 "life cycle" and its role in protein biosynthesis.
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