Charge-Changing Perturbations and Path Sampling via Classical Molecular Dynamic Simulations of Simple Guest-Host...

Area of Science:

• Computational chemistry
• Molecular modeling
• Biophysics

Background:

• Two primary methods, alchemical and pathway, are used for biomolecular free-energy calculations.
• Alchemical methods are suited for small ligands in buried sites, while pathway methods are for large ligands on surfaces.
• Electrostatic energy representation in periodic simulations introduces artifacts, especially with net charge changes.

Purpose of the Study:

• To investigate the effectiveness of instantaneous correction schemes in mitigating electrostatic artifacts.
• To determine if these artifacts affect both alchemical and pathway methods.

Main Methods:

• Utilized simple test systems for biomolecular free-energy calculations.
• Applied instantaneous correction schemes, including co-alchemical perturbation of ions.
• Analyzed electrostatic energy representations in periodic simulation boxes.

Main Results:

• Instantaneous correction schemes, even without net charge change, reduce but do not fully eliminate electrostatic artifacts.
• Pathway methods for free-energy calculations exhibit similar electrostatic artifacts as alchemical methods.

Conclusions:

• Current instantaneous correction schemes are insufficient to completely remove electrostatic artifacts in free-energy calculations.
• Both alchemical and pathway methods are susceptible to these artifacts, necessitating further method development.