Due to the complexity and insufficient compute power alchemical free energy simulations are not routinely applied in early stage drug discovery. In the recent release of MOE we added a streamlined interface to setup GPU enabled molecular dynamics simulations based on the Thermodynamic Integration (TI) method in AMBER18. The workflow includes structure preparation, ligand parameterization, simulation planning and analysis. Free energy calculations are known to be extremely sensitive and come with a high failure rate. For optimal<br/>simulation planning we designed a scoring function to minimize 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 this integral can be achieved with spectral accuracy. The workflow was validated through the calculation of absolute binding energies of 34 ligands of the p38 MAP Kinase and compared to experimental data.

Optimizing simulations protocols for relative free energy calculations

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.