Free Energy Calculations with Thermodynamic Integration in MOE using AMBER
Until the advent of GPU-accelerated molecular dynamics, alchemical free energy simulations had not been routinely applied in early-stage drug discovery. While this GPU acceleration made such calculations more feasible, the complexity of the protocols and uncertainty regarding optimal parameters are a lingering problem. In the recently released MOE 2019, a streamlined interface was added to set up free alchemical energy calculations dynamics simulations based on the Thermodynamic Integration (TI) method in AMBER 18. The workflow includes structure preparation, ligand parameterization, simulation planning, and analysis. Free energy calculations are known to be extremely sensitive and have a high failure rate. We present an optimal simulation planning methodology that minimizes the expected error for a given system based on the available simulation resources (number of GPUs, nodes, etc.). Another major source of error is the simulation instability due to an imbalance between the electrostatic and van der Waals forces. Optimization of the AMBER soft-core potential resulted in much higher simulation stability and hence lower curvature of the potential function. In conjunction with Fejér numerical integration, the evaluation of the alchemical integral can be achieved with spectral accuracy. The methodology was validated through the calculation of relative binding energies of 34 ligands of the p38 MAP Kinase and compared to experimental data.
Airdate: October 1, 2019
