Effects of Conformational Sampling on Computing Redox Properties Using Linear Response Approach

Area of Science:

• Computational Chemistry
• Biophysical Chemistry
• Quantum Chemistry

Background:

• Redox processes are fundamental in chemical and biochemical reactions.
• Linear response approximation (LRA) is a common method for calculating redox free energy changes.
• Accurate LRA requires balancing computational cost with precise conformational and energy-gap sampling.

Purpose of the Study:

• To evaluate the impact of different conformational sampling strategies on redox property calculations.
• To compare molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations for redox potential determination.
• To assess the influence of QM region size in QM/MM simulations on redox behavior.

Main Methods:

• Conformational sampling using both MM and QM/MM simulations for small, biologically relevant redox-active molecules in aqueous solution.
• Calculation of one-electron oxidation free energies and potentials.
• Systematic variation of the quantum mechanical (QM) region size within QM/MM simulations.

Main Results:

• A consistent difference of approximately 0.2-0.4 V in the free energy of oxidation and oxidation potential was observed between QM/MM and MM sampling methods.
• The choice of sampling strategy (MM vs. QM/MM) significantly impacts calculated redox properties.
• QM/MM energy-gap sampling variations showed an effect on overall redox behavior.

Conclusions:

• Computationally less expensive MM sampling can be adequate for calculating redox properties of small molecules.
• A system-specific correction factor is recommended when using MM sampling for accurate redox potential prediction.
• This finding suggests a more efficient computational approach for studying redox-active molecules.