Molecular Dynamics of Enzyme-Substrate Complexes in Guanosine Trifosphate-Binding Proteins

The dynamic properties of enzyme-substrate complexes in the reaction of the hydrolysis of guanosine triphosphate (GTP) are compared by the native Ras enzyme and its variant G12VRas with oncogenic point substitution using molecular dynamic methods with potentials constructed according to the theory of quantum mechanics/molecular mechanics (QM/MM). Molecular models of systems including the GTP-binding protein Ras, the GAP accelerator protein, the GTP substrate, and the catalytic water molecule are constructed based on the atomic coordinates of the complex from the database of protein structures. An analysis of the obtained distributions along molecular dynamics trajectories for the distances between the oxygen atom of the catalytic water molecule in the active center of the complex and the phosphorus atom of the γ-phosphate group of GTP showed that the G12V substitution leads to the growth of populations with large distances between the reactants, thus reducing the proportion of the fraction of reactive conformations for the hydrolysis reaction.