Electrostatic free energies in translational GTPases: Classic allostery and the rest

• Published in: Biochimica et biophysica acta Vol. 1850; no. 5; pp. 1006 - 1016
• Main Authors: Simonson, Thomas, Aleksandrov, Alexey, Satpati, Priyadarshi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015; Elsevier
• Subjects: adenosinetriphosphatase; Allosteric Regulation; Archaeal Proteins - chemistry; Archaeal Proteins - metabolism; Biochemistry, Molecular Biology; computational chemistry; continuum electrostatics; Energy Transfer; Enzyme Activation; genetic code; Gibbs free energy; GTP Phosphohydrolases - chemistry; GTP Phosphohydrolases - metabolism; Guanosine Diphosphate - chemistry; Guanosine Diphosphate - metabolism; guanosine triphosphate; Guanosine Triphosphate - chemistry; Guanosine Triphosphate - metabolism; guanosinetriphosphatase; induced fit; ions; Life Sciences; Ligands; magnesium; Magnesium - chemistry; molecular dynamics; Molecular Dynamics Simulation; Molecular recognition; Peptide Initiation Factors - chemistry; Peptide Initiation Factors - metabolism; Protein Conformation; Static Electricity; Structure-Activity Relationship; Thermodynamics; translation (genetics); IS/OS; MDFE; PBFE; MD; ATP/GTP; Molecular recognition; induced fit; molecular dynamics; computational chemistry; aIF2/aIF5B; continuum electrostatics
• ISSN: 0304-4165; 0006-3002; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2014.07.006

GTPases typically switch between an inactive, OFF conformation and an active, ON conformation when a GDP ligand is replaced by GTP. Their ON/OFF populations and activity thus depend on the stabilities of four protein complexes, two apo-protein forms, and GTP/GDP in solution. A complete characterization is usually not possible experimentally and poses major challenges for simulations. We review the most important methodological challenges and we review thermodynamic data for two GTPases involved in translation of the genetic code: archaeal Initiation Factors 2 and 5B (aIF2, aIF5B). One main challenge is the multiplicity of states and conformations, including those of GTP/GDP in solution. Another is force field accuracy, especially for interactions of GTP/GDP with co-bound divalent Mg2+ ions. The calculation of electrostatic free energies also poses specific challenges, and requires careful protocols. For aIF2, experiments and earlier simulations showed that it is a “classic” GTPase, with distinct ON/OFF conformations that prefer to bind GTP and GDP, respectively. For aIF5B, we recently proposed a non-classic mechanism, where the ON/OFF states differ only in the protonation state of Glu81 in the nucleotide binding pocket. This model is characterized here using free energy simulations. The methodological analysis should help future studies, while the aIF2, aIF5B examples illustrate the diversity of ATPase/GTPase mechanisms. This article is part of a Special Issue entitled Recent developments of molecular dynamics. •GTPase/ATPase mechanism can be described by a general thermodynamic framework.•GTPase simulations are a challenge for standard force fields and free energy methods.•We use free energy simulations to characterize two GTPases: one classic, one non-classic.