Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations.

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Quantum Mechanics

Background:

• Calculating binding free energies with quantum-mechanical (QM) methods is computationally expensive.
• Molecular mechanics (MM) methods are faster but less accurate for binding free energy calculations.

Purpose of the Study:

• To investigate the acceleration of QM binding free energy calculations using nonequilibrium (NE) molecular dynamics simulations.
• To assess the accuracy of QM/MM free energy corrections derived from NE simulations.

Main Methods:

• Binding free energies were calculated using molecular mechanics (MM) with free energy perturbation.
• QM/MM free energy corrections were estimated using NE molecular dynamics simulations and Jarzynski's equality.
• Ligands were modeled at the semiempirical PM6-DH+ QM level within a QM/MM framework.

Main Results:

• The NE simulation approach provided MM → QM/MM free energy corrections consistent with other methods.
• Sufficient precision (0.3 kJ/mol) was achievable with an appropriate number of NE simulations (36-324).
• A total simulation length of 20 ps was adequate for most ligands studied.

Conclusions:

• Nonequilibrium molecular dynamics simulations offer a viable strategy for accelerating QM binding free energy calculations.
• Jarzynski's equality can be effectively employed to obtain accurate QM/MM free energy corrections.
• This approach balances computational cost and accuracy for binding free energy determination.