Improved precision and efficiency of free energy calculations for small systems using lambda-scaled atomic masses and...

Area of Science:

• Computational chemistry
• Molecular modeling

Background:

• Free-energy calculations are crucial for drug discovery and materials science.
• Molecular dynamics (MD) simulations with free-energy perturbations (FEPs) are widely used.
• Accurate treatment of simulation parameters is essential for reliable results.

Purpose of the Study:

• To investigate the impact of atomic mass treatment in MD-based FEPs for small molecules.
• To improve the efficiency and accuracy of free-energy calculations.
• To explore methods for accelerating FEP convergence in flexible molecules.

Main Methods:

• Single topology FEPs were employed for molecular dynamics simulations.
• Atomic masses of mutated atoms were scaled with the lambda variable.
• Relative hydration free energy differences were calculated for ethane and n-propane.
• Constrained conformations were utilized to improve FEP convergence for cyclic alkanes.

Main Results:

• Scaling atomic mass significantly improves gas-phase simulation reversibility in FEPs.
• This mass scaling method enhances the accuracy of hydration free energy difference calculations.
• Standard FEPs require prohibitively long simulation times for flexible cyclic alkanes.
• Constrained conformation pathways offer a viable alternative for accelerating FEP convergence.

Conclusions:

• Appropriate treatment of atomic masses is critical for accurate MD/FEP calculations.
• Mass scaling is a valuable technique for improving FEP reversibility and accuracy.
• Alternative free energy pathways are necessary for efficient FEP simulations of flexible molecules.