Evaluating the active site-substrate interplay between x-ray crystal structure and molecular dynamics in chorismate...

Area of Science:

• Computational enzymology
• Biophysical chemistry
• Structural biology

Background:

• Accurate quantum mechanical (QM) models of enzyme active sites require precise identification of key residues, solvents, and cofactors.
• Interatomic van der Waals contacts have been used to guide QM model design, but their reliability may be affected by protein structural dynamics.

Purpose of the Study:

• To investigate the influence of protein structural dynamics on ligand-residue interatomic contacts and their predictive power for QM model design.
• To compare interatomic contacts from X-ray crystallography with those from molecular dynamics (MD) simulations for chorismate mutase.
• To evaluate the correlation between interatomic contacts and ab initio interaction energies.

Main Methods:

• Analysis of ligand-residue interatomic contacts in an X-ray crystal structure of chorismate mutase.
• Comparison with contacts derived from multiple structures obtained via molecular dynamics (MD) simulations.
• Computation of ab initio ligand-residue interaction energies using symmetry-adapted perturbation theory (SAPT) on selected structures.

Main Results:

• Ligand-residue interatomic contacts from X-ray structures do not accurately predict contacts observed in MD simulation frames.
• Variability in interatomic contacts across different structures did not correlate with variability in calculated interaction energies.
• Interaction energies provide a more robust measure for ranking residue importance.

Conclusions:

• Static crystal structures may not fully capture the dynamic nature of enzyme active sites relevant for QM modeling.
• Ab initio interaction energies are a more reliable metric than interatomic contacts for assessing residue contributions in computational enzymology.
• This study highlights the utility of interaction energies for future QM/MM modeling workflows.