Redox potential replica exchange molecular dynamics at constant pH in AMBER: Implementation and validation.

Area of Science:

• Computational Chemistry
• Biophysical Chemistry
• Molecular Dynamics

Background:

• Redox processes are crucial in various scientific fields, including biomedicine and chemical analysis.
• Experimental redox studies often require controlled pH conditions, necessitating supportive computational techniques.
• Existing computational methods lack efficient support for simultaneous constant redox potential and pH simulations.

Purpose of the Study:

• To implement and validate advanced computational methods for simulating systems at constant redox potential and pH.
• To enhance the predictive accuracy of standard redox potentials (E°) and pKa values.
• To provide atomic-level insights into experimentally observed redox and protonation behaviors.

Main Methods:

• Implementation of discrete redox and protonation states for constant redox potential Molecular Dynamics (CEMD).
• Development of coupled constant pH and constant redox potential MD (C(pH,E)MD).
• Application of Replica Exchange MD along the redox potential dimension (E-REMD) within the AMBER software package.
• Validation using a heme-containing peptide (NAcMP8).

Main Results:

• Accurate prediction of standard redox potentials (E°) and pKa values, comparable to existing constant pH methods.
• Correctly described the interdependence of redox state and protonation: reduction increases nearby pKa, protonation increases adjacent E°.
• Demonstrated that E-REMD achieves faster statistical convergence compared to CEMD and C(pH,E)MD.
• Highlighted the high performance of GPU-accelerated calculations over CPU.

Conclusions:

• The developed CEMD, C(pH,E)MD, and E-REMD methods provide robust tools for redox and pH simulations.
• These methods facilitate validation of experimental findings and offer deeper mechanistic understanding.
• E-REMD shows superior efficiency for achieving converged results in redox potential simulations.