Constant pH replica exchange molecular dynamics in biomolecules using a discrete protonation model

Area of Science:

• Computational Chemistry
• Biophysics
• Molecular Dynamics

Background:

• Accurate sampling of protonation states and molecular conformations is crucial for understanding biological systems.
• Traditional molecular dynamics methods can suffer from slow conformational sampling and protonation state transitions.

Purpose of the Study:

• To introduce and validate a novel constant pH replica exchange molecular dynamics (REMD) method.
• To improve the efficiency of coupled protonation and conformational state sampling in molecular simulations.

Main Methods:

• Developed a constant pH REMD method combining conformational sampling at constant pH with a temperature ladder.
• Applied the method to seven diverse biological systems, including small model compounds and a heptapeptide.

Main Results:

• The constant pH REMD method accurately predicted pKa values for model compounds.
• Demonstrated faster convergence compared to constant pH molecular dynamics (MD).
• Showcased superior efficiency in sampling both conformational and protonation states for a heptapeptide.

Conclusions:

• The proposed constant pH REMD method effectively enhances the sampling of coupled protonation and conformational states.
• This technique offers a more efficient alternative to conventional MD for studying biological systems where protonation is critical.