Force Field Limitations of All-Atom Continuous Constant pH Molecular Dynamics

Area of Science:

• Computational Biology
• Biophysics
• Molecular Dynamics

Background:

• Constant pH molecular dynamics simulations are crucial for studying pH-dependent biological events.
• Protein pKa values are sensitive to force fields and water models due to electrostatic and solvation effects.

Purpose of the Study:

• To investigate the force field dependence of all-atom particle mesh Ewald (PME) continuous constant pH (PME-CpHMD) simulations.
• To evaluate the accuracy of different Amber force fields and water models for pKa calculations in a mini-protein.

Main Methods:

• Performed replica-exchange titration simulations using Amber ff19sb and ff14sb force fields with corresponding water models.
• Analyzed pKa values for specific residues (His166, Glu141, Glu161) in the mini-protein BBL.
• Investigated the effect of atom-pair specific Lennard-Jones corrections (NBFIX) on pKa calculations.

Main Results:

• Both Amber ff19sb and ff14sb force fields showed overestimated pKa downshifts for key residues.
• ff19sb with OPC water demonstrated higher accuracy compared to ff14sb with TIP3P water.
• NBFIX corrections partially mitigated errors associated with salt-bridge interactions.

Conclusions:

• The choice of protein force field and water model significantly influences the accuracy of pKa predictions in constant pH simulations.
• Improvements in force fields are essential for reliable calculations of protein protonation equilibria.
• Accurate pKa calculations are vital for understanding pH-mediated biological mechanisms.