Quantitative description of side chain effects on binding to protein

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Physics

Background:

• Tyrosyl-tRNA synthetase plays a crucial role in protein synthesis by catalyzing the attachment of tyrosine to its cognate tRNA.
• Understanding the binding interactions of substrates and transition states is essential for elucidating enzyme mechanisms.
• Previous studies have reported binding free energy changes (delta delta G) for transition state binding, but a quantitative description based on molecular properties was lacking.

Purpose of the Study:

• To quantitatively describe the transition state binding of ATP and tyrosine by tyrosyl-tRNA synthetase using the intermolecular force (IMF) equation.
• To identify the major molecular factors governing the binding affinity and specificity of tyrosyl-tRNA synthetase.

Main Methods:

• Analysis of previously reported delta delta G values for transition state binding.
• Application of the intermolecular force (IMF) equation to correlate binding free energy with molecular properties.
• Evaluation of contributions from polarizability, ionic interactions, steric effects, and hydrogen bonding.

Main Results:

• The intermolecular force (IMF) equation quantitatively describes the observed delta delta G values.
• Polarizability, ionic side chains, and steric effects were identified as the predominant factors influencing binding.
• Dispersion forces and ion/dipole and ion-induced/dipole interactions appear to be the primary driving forces for binding.

Conclusions:

• The binding of ATP and tyrosine to tyrosyl-tRNA synthetase transition states is well-described by intermolecular forces.
• Enzyme-ligand interactions are governed by a combination of electrostatic, polar, and non-polar forces.
• Hydrogen bonding likely plays a minor role in the overall binding energy of this system.