Assessment of Binding Affinity via Alchemical Free-Energy Calculations

Abstract

Free energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented , constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace and OpenMM and uses the AMBER14SB and GAFF2.1

Best Practices for Alchemical Free Energy Calculations [Article v1.0]

“…1 E) [12][13][14]; • small alchemical modifications can be made between chemically related ligands to estimate relative differences in binding free energies ( Fig. 1 F) [15][16][17][18][19].…”

“…Subsequent work in the 2000s led to improved implementations of alchemical methods in popular biomolecular simulation packages [15,[30][31][32][33][34][35]. This foundational work, combined with the methodological, technological, and hardware improvements of the last 5-10 years, has led to an explosion of interest and direct commercial application of these technologies [15,19,[36][37][38][39].…”

“…Running binding free energy calculations in a drug discovery application will typically require the use of software or tools to facilitate the large number of calculations. Commercial implementations such as FEP+, OpenEye Tools, or Flare allow for a fast setup and deployment to GPU hardware in minutes, but may have limited ability to customize calculations [15,19]. Commercial tools can be expensive in some cases, but non-commercial tools are becoming more straight forward to use to run alchemical free energy calculations [17-19, 34, 90-92].…”

Non-equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software

“…S8). Given that the state-of-the-art accuracy reached for relative protein-ligand binding affinity calculations is on average ∼ 1 kcal∕mol [18,46,47], it is expected that absolute free energy calculations requiring larger perturbations would show a similar or larger deviation from experiment.…”

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo

“…FEP calculations typically use molecular dynamics (MD) to efficiently capture the coupled and concerted motion of atomistic configurations. 2,3 However, water molecules that are buried deep within the interiors of proteins can have residence times as long as hundreds of microseconds 4 -well beyond the typical sampling time of FEP calculations. As a result, FEP transformations that modify or displace buried water have remained inaccurate as well as sensitive to the initial placement of water inside the protein.…”