Comparative structural dynamic analysis of GTPases

PLoS Comput Biol. 2018 Nov 9;14(11):e1006364. doi: 10.1371/journal.pcbi.1006364. eCollection 2018 Nov.


GTPases regulate a multitude of essential cellular processes ranging from movement and division to differentiation and neuronal activity. These ubiquitous enzymes operate by hydrolyzing GTP to GDP with associated conformational changes that modulate affinity for family-specific binding partners. There are three major GTPase superfamilies: Ras-like GTPases, heterotrimeric G proteins and protein-synthesizing GTPases. Although they contain similar nucleotide-binding sites, the detailed mechanisms by which these structurally and functionally diverse superfamilies operate remain unclear. Here we compare and contrast the structural dynamic mechanisms of each superfamily using extensive molecular dynamics (MD) simulations and subsequent network analysis approaches. In particular, dissection of the cross-correlations of atomic displacements in both the GTP and GDP-bound states of Ras, transducin and elongation factor EF-Tu reveals analogous dynamic features. This includes similar dynamic communities and subdomain structures (termed lobes). For all three proteins the GTP-bound state has stronger couplings between equivalent lobes. Network analysis further identifies common and family-specific residues mediating the state-specific coupling of distal functional sites. Mutational simulations demonstrate how disrupting these couplings leads to distal dynamic effects at the nucleotide-binding site of each family. Collectively our studies extend current understanding of GTPase allosteric mechanisms and highlight previously unappreciated similarities across functionally diverse families.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • GTP Phosphohydrolases / chemistry*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Guanosine Diphosphate / metabolism
  • Guanosine Triphosphate / metabolism
  • Molecular Dynamics Simulation
  • Mutation
  • Nucleotides / metabolism
  • Peptide Elongation Factor Tu / metabolism
  • Principal Component Analysis
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • Signal Transduction
  • Transducin / metabolism
  • ras Proteins / metabolism


  • Nucleotides
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • Peptide Elongation Factor Tu
  • Transducin
  • ras Proteins