Guidelines for Free-Energy Calculations Involving Charge Changes.

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Statistical Mechanics

Background:

• Coulomb interactions in molecular simulations are approximated due to finite box sizes, leading to artifacts.
• Existing methods for long-range electrostatics and lattice-sum methods introduce finite-size-related artifacts, especially in free-energy calculations involving charge changes.
• These artifacts can bias sampling and lead to inaccurate results in molecular simulations.

Purpose of the Study:

• To investigate the role of finite-size artifacts in molecular simulations under conditions of overall neutral boxes.
• To assess the impact of these artifacts on both free-energy calculations and ensemble sampling.
• To determine practical guidelines for mitigating finite-size artifacts in molecular simulations.

Main Methods:

• Utilized two previously described model systems for investigation.
• Performed molecular simulations focusing on systems with overall neutral boxes.
• Analyzed results in the context of both free-energy calculations and direct sampling.

Main Results:

• Finite-size artifacts can be significantly reduced by ensuring no net charge changes occur within a neutral simulation box, provided the box is sufficiently large.
• Addition of salt to the simulation environment can further alleviate remaining artifacts in sampling and free-energy differences.
• The study identified conditions under which finite-size artifacts are minimized.

Conclusions:

• Maintaining overall neutral simulation boxes and avoiding net charge changes are key strategies to minimize finite-size artifacts.
• Sufficiently large simulation box sizes are essential for accurate results.
• Salt addition can serve as an additional tool to improve the accuracy of molecular simulations, particularly for free-energy calculations and sampling.