Acidic range titration of HEWL using a constant-pH molecular dynamics method

Area of Science:

• Biophysics
• Computational Chemistry
• Protein Dynamics

Background:

• Accurate prediction of protein behavior at varying pH is crucial for understanding biological function.
• Molecular dynamics (MD) simulations are powerful tools for studying protein structure and dynamics.
• Proton tautomerism and constant-pH simulations present significant computational challenges.

Purpose of the Study:

• To apply the stochastic constant-pH molecular dynamics method, including proton tautomerism, to a protein system for the first time.
• To investigate the acidic titration of hen egg-white lysozyme (HEWL) under various conditions.
• To compare the performance of generalized reaction field (GRF) and particle mesh Ewald (PME) methods for electrostatic treatment in constant-pH MD.

Main Methods:

• Stochastic constant-pH molecular dynamics (MD) simulations incorporating proton tautomerism.
• Acidic titration of hen egg-white lysozyme (HEWL).
• Application of generalized reaction field (GRF) and particle mesh Ewald (PME) methods for long-range electrostatics.
• Analysis of secondary structure stability and alpha-helix stability at acidic pH.

Main Results:

• The GRF method yielded better pKa prediction accuracy (0.82 RMSD) compared to PME (1.13 RMSD).
• Increasing the dielectric constant in PME simulations did not significantly improve pKa prediction.
• HEWL exhibited remarkable stability in the acidic pH range, with beta-sheet strands being less stable than alpha-helices.

Conclusions:

• The stochastic constant-pH MD method with proton tautomerism is applicable to protein systems.
• GRF is a more accurate method than PME for electrostatic treatment in this specific constant-pH MD application.
• HEWL's secondary structure stability varies with pH, with a less stable beta-domain at acidic conditions.