CHARMM-GUI Free Energy Calculator for Practical Ligand Binding Free Energy Simulations with AMBER

Alchemical
free energy methods, such as free energy perturbation
(FEP) and thermodynamic integration (TI), become increasingly popular
and crucial for drug design and discovery. However, the system preparation
of alchemical free energy simulation is an error-prone, time-consuming,
and tedious process for a large number of ligands. To address this
issue, we have recently presented CHARMM-GUI Free Energy Calculator that can provide input and postprocessing scripts for NAMD and GENESIS
FEP molecular dynamics systems. In this work, we extended three submodules
of Free Energy Calculator to work with the full suite
of GPU-accelerated alchemical free energy methods and tools in AMBER,
including input and postprocessing scripts. The BACE1 (β-secretase
1) benchmark set was used to validate the AMBER-TI simulation systems
and scripts generated by Free Energy Calculator.
The overall results of relatively large and diverse systems are almost
equivalent with different protocols (unified and split) and with different
timesteps (1, 2, and 4 fs), with R2 >
0.9. More importantly, the average free energy differences between
two protocols are small and reliable with four independent runs, with
a mean unsigned error (MUE) below 0.4 kcal/mol. Running at least four
independent runs for each pair with AMBER20 (and FF19SB/GAFF2.1/OPC
force fields), we obtained a MUE of 0.99 kcal/mol and root-mean-square
error of 1.31 kcal/mol for 58 alchemical transformations in comparison
with experimental data. In addition, a set of ligands for T4-lysozyme
was used to further validate our free energy calculation protocol
whose results are close to experimental data (within 1 kcal/mol).
In summary, Free Energy Calculator provides a user-friendly
web-based tool to generate the AMBER-TI system and input files for
high-throughput binding free energy calculations with access to the
full set of GPU-accelerated alchemical free energy, enhanced sampling,
and analysis methods in AMBER.