Predicting Binding Free Energies: Frontiers and Benchmarks

Abstract

Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions among its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in early-stage drug discovery. However, many hurdles remain in making them a robust and reliable tool. In this review, we highlight key challenges of these calculations, discuss some examples of these challenges, and call for the designation of standard community benchmark test systems that will help the research community generate and evaluate progress. In our view, progress will require careful assessment and evaluation of new methods, force fields, and modeling innovations on well-characterized benchmark systems, and we lay out our vision for how this can be achieved.

Keywords: alchemical; benchmark; binding affinity; binding free energy; biomolecular interactions; molecular simulation.

Figure 1

OA, TEMOA, and CB7 hosts. Shown are the hosts which are the focus of our host-guest benchmark sets – two variants of the octa-acid GDCC, and CB7, a cucurbituril. Guest structures are available in the supplemental material.

Figure 2

Benzene and hexylbenzene in the lysozyme L99A site, and phenol and 4,5,6,7-tetrahydroindole in the L99A/M102Q site (PDBs 4W52, 4W59, 1LI2, and 3HUA, respectively). The binding site shape is shown as a semi-transparent surface, and the protein shown with cartoons. In both cases, the structure with the smaller ligand is shown in green and that with the larger ligand is shown in blue, and the larger ligand induces a motion of helix F bordering the binding site. Phenol and 4,5,6,7-tetrahydroindole both also bind with an ordered water, though this does not occur for all ligands in the polar L99A/M102Q site.