All-Atom Continuous Constant pH Molecular Dynamics With Particle Mesh Ewald and Titratable Water.

Area of Science:

• Computational chemistry and biophysics
• Molecular dynamics simulations
• Protein pKa calculations

Background:

• Controlling solution pH in biomolecular simulations is crucial but challenging.
• Existing constant pH molecular dynamics methods often lack accuracy due to implicit solvent or truncated electrostatics.
• A need exists for more general and accurate pH control in molecular simulations.

Purpose of the Study:

• To implement the particle mesh Ewald (PME) scheme into the all-atom continuous constant pH molecular dynamics (CpHMD) method.
• To enable accurate and efficient pH-controlled molecular dynamics simulations using standard MD engines.
• To validate the performance of PME-based CpHMD for calculating protein pKa values.

Main Methods:

• Integration of the PME electrostatic scheme into the all-atom CpHMD framework.
• Performance evaluation using pH replica-exchange CpHMD simulations with titratable water.
• Testing on a set of proteins (HP36, BBL, HEWL, SNase) with 10 ns sampling per replica.

Main Results:

• PME-based CpHMD achieved converged pKa values for most sites.
• Average absolute and root-mean-square deviations from experimental pKa values were 0.61 and 0.77, respectively.
• Linear regression showed a high correlation (0.79) between calculated and experimental pKa shifts.

Conclusions:

• PME-based CpHMD provides a general and computationally efficient tool for pH-controlled simulations.
• The method enables atomic-level insights into pH-dependent behavior of various macromolecular systems.
• Further improvements can be achieved by addressing structure relaxation sampling during protonation state changes.