Fully Atomistic Multiscale Approach for pK Prediction.

Area of Science:

• Biochemistry
• Computational Chemistry
• Structural Biology

Background:

• Protein structure and function are heavily influenced by the ionization state of titratable amino acids.
• Accurate characterization of ionizable group pKa values within proteins is essential for understanding biological processes.
• Predicting deprotonation free energies and pKa values computationally remains a significant challenge.

Purpose of the Study:

• To develop and validate a hybrid quantum/classical methodology for calculating deprotonation free energies.
• To assess the accuracy of the proposed method for small molecules and amino acid residues in solution and within a protein environment.
• To investigate the microscopic determinants of pKa shifts in proteins.

Main Methods:

• A hybrid quantum/classical approach was employed to compute deprotonation free energies.
• The method was applied to small molecules (formic acid, methylammonium, methanethiol) and amino acids (aspartic acid, lysine) in solution.
• Calculations were extended to aspartic/glutamic acid residues within hen egg white lysozyme.

Main Results:

• The method achieved good agreement with experimental pKa estimates for small molecules.
• Calculated pKa values for single amino acids showed systematic shifts compared to experimental data, suggesting limitations in classical force fields for hydrophobic/polar interactions.
• The computed pKa shifts within lysozyme accurately reproduced experimental changes (within 1 pKa unit), even for large shifts.

Conclusions:

• The hybrid quantum/classical method provides a robust approach for calculating deprotonation free energies and pKa values.
• While accurate for small molecules, the method highlights potential inaccuracies in classical force fields for protein environments.
• The study successfully demonstrates the ability to predict environmentally induced pKa shifts in proteins, offering valuable insights into protein function.