Repulsive Soft-Core Potentials for Efficient Alchemical Free Energy Calculations

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Biophysics

Background:

• Alchemical free energy (FE) simulations are crucial for understanding molecular interactions.
• Current soft-core potentials introduce non-linearity, complicating FE calculations and reducing efficiency.

Purpose of the Study:

• To develop a novel repulsive soft-core potential for alchemical FE simulations.
• To enhance the efficiency and accuracy of FE calculations using Bennett acceptance ratio (BAR), free energy perturbation (FEP), and thermodynamic integration (TI) methods.

Main Methods:

• Development of the Gaussian soft-core (GSC) potential with tunable parameters.
• Linearization of the hybrid Hamiltonian with respect to the coupling parameter λ.
• Application of GSC potential to calculate free energies of annihilation for small molecules and protein mutations.

Main Results:

• The GSC potential ensures linearity of the hybrid Hamiltonian, enabling direct application of standard FE methods.
• Accurate free energy calculations were achieved for 13 small molecules and a protein side chain mutation.
• The GSC potential, combined with a TI integrand strategy, significantly reduces the number of required λ simulations compared to existing methods.

Conclusions:

• The GSC potential offers a more efficient and accurate approach for alchemical free energy simulations.
• This method simplifies FE calculations, making them more accessible and reliable for complex systems.
• The GSC potential represents a significant advancement in computational chemistry for molecular modeling and drug discovery.