Simulating GTP:Mg and GDP:Mg with a simple force field: a structural and thermodynamic analysis

Area of Science:

• Computational Chemistry
• Biophysics
• Molecular Dynamics

Background:

• Di- and tri-phosphate nucleotides, often Mg(2+)-bound, are crucial cofactors for proteins like GTPases.
• Proteins distinguish between nucleotide diphosphates (NDP) and nucleotide triphosphates (NTP), triggering conformational changes.
• Accurate simulation of these nucleotide-protein complexes requires precise force fields for reliable free energy calculations.

Purpose of the Study:

• To investigate the influence of two Mg(2+) coordination modes (Inner Sphere and Outer Sphere) on unbound GDP and GTP.
• To compare the binding of GTP:Mg and GDP:Mg complexes under different coordination modes.
• To evaluate the effect of a key force field parameter (Mg:oxygen van der Waals distance Rmin) on binding affinities and coordination preferences.

Main Methods:

• Utilized a simple, fixed-charge force field for molecular simulations.
• Examined direct (Inner Sphere) and indirect (Outer Sphere) Mg(2+) coordination modes for GDP and GTP.
• Performed free energy calculations and analyzed binding affinities and coordination states.

Main Results:

• GTP preferentially binds with Inner Sphere Mg(2+) coordination, supported by combined simulation and experimental data.
• Adjusting the Mg:oxygen van der Waals distance (Rmin) improved Mg:oxygen distances and binding affinities for both GTP:Mg and GDP:Mg.
• The force field parameter Rmin did not resolve the discrepancy in the calculated GTP/GDP affinity difference compared to experimental values.

Conclusions:

• The Mg(2+) coordination mode significantly impacts nucleotide binding preferences.
• While force field parameterization can improve binding affinity calculations, accurately capturing the GTP/GDP affinity difference remains challenging.
• Further refinement of force fields is necessary for precise simulation of nucleotide-protein interactions.