title: Electrostatic free energies in translational GTPases: Classic allostery and the rest.
abstract: 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 Mg(2+) 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.
authors.affiliation: Laboratoire de Biochimie (CNRS unit 7654), Department of Biology, Ecole Polytechnique, 91128 Palaiseau, France. Electronic address: thomas.simonson@polytechnique.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonson
authors.affiliation: Laboratoire de Biochimie (CNRS unit 7654), Department of Biology, Ecole Polytechnique, 91128 Palaiseau, France.
authors.forename: Alexey
authors.initials: A
authors.lastname: Aleksandrov
authors.affiliation: Laboratoire de Biochimie (CNRS unit 7654), Department of Biology, Ecole Polytechnique, 91128 Palaiseau, France; Department of Cell and Molecular Biology, University of Uppsala, Sweden.
authors.forename: Priyadarshi
authors.initials: P
authors.lastname: Satpati
mesh_terms: D000494:Allosteric Regulation; D019843:Archaeal Proteins / Q000737:chemistry* / Q000378:metabolism; D004735:Energy Transfer; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000737:chemistry* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008274:Magnesium / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010448:Peptide Initiation Factors / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D019843:Archaeal Proteins; D008024:Ligands; D010448:Peptide Initiation Factors; C116557:initiation factor 2, archaeal; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D008274:Magnesium
keywords: Molecular recognition; computational chemistry; continuum electrostatics; induced fit; molecular dynamics