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Electrostatic free energies in translational GTPases: Classic allostery and the rest
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
2015 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1850, no 5, 1006-1016 p.Article, review/survey (Refereed) Published
Abstract [en]

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. (C) 2014 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
2015. Vol. 1850, no 5, 1006-1016 p.
Keyword [en]
Molecular recognition, induced fit, molecular dynamics, continuum electrostatics, computational chemistry
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-251671DOI: 10.1016/j.bbagen.2014.07.006ISI: 000350706700016OAI: oai:DiVA.org:uu-251671DiVA: diva2:807805
Available from: 2015-04-24 Created: 2015-04-23 Last updated: 2015-04-24Bibliographically approved

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