Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations

Abstract

Alchemical absolute binding free energy calculations are of increasing interest in drug discovery. These calculations require restraints between the receptor and ligand to restrict their relative positions and, optionally, orientations. Boresch restraints are commonly used, but they must be carefully selected in order to sufficiently restrain the ligand and to avoid inherent instabilities. Applying multiple distance restraints between anchor points in the receptor and ligand provides an alternative framework without inherent instabilities which may provide convergence benefits by more strongly restricting the relative movements of the receptor and ligand. However, there is no simple method to calculate the free energy of releasing these restraints due to the coupling of the internal and external degrees of freedom of the receptor and ligand. Here, a method to rigorously calculate free energies of binding with multiple distance restraints by imposing intramolecular restraints on the anchor points is proposed. Absolute binding free energies for the human macrophage migration inhibitory factor/MIF180, system obtained using a variety of Boresch restraints and rigorous and nonrigorous implementations of multiple distance restraints are compared. It is shown that several multiple distance restraint schemes produce estimates in good agreement with Boresch restraints. In contrast, calculations without orientational restraints produce erroneously favorable free energies of binding by up to approximately 4 kcal mol–1. These approaches offer new options for the deployment of alchemical absolute binding free energy calculations.

Expanded ensemble predictions of absolute binding free energies in the SAMPL9 host–guest challenge

“…56 While this restraint scheme gives an exact expression for the restraint free energy, we deemed it very difficult to choose the anchor points a priori, especially given the our imprecise knowledge of the binding pose (which is likely to be highly dynamic). For an excellent recent comparison of restraint schemes for absolute binding free energies, we refer the reader to Clark et al 57 In SAMPL6, which also featured highly carboxylated hostsocta-acid (OA) and tetramethyl octa-acid (TEMOA)-participants using GAFF/AM1-BCC with TIP3P consistently underestimated DG (i.e. predicted tighter binding), 4 similar to our results.…”

“…56 While this restraint scheme gives an exact expression for the restraint free energy, we deemed it very difficult to choose the anchor points a priori , especially given the our imprecise knowledge of the binding pose (which is likely to be highly dynamic). For an excellent recent comparison of restraint schemes for absolute binding free energies, we refer the reader to Clark et al 57…”

Addressing Suboptimal Poses in Nonequilibrium Alchemical Calculations

“…The calculation of accurate absolute binding free energies of protein–ligand complexes is an essential and challenging task in computer-aided drug design (CADD). Many algorithms have been developed for this purpose, ranging from end-point alchemical methods − to collective variable (CV)-based enhanced sampling algorithms. − Ease of use, speed, automation, and reliability of the algorithm are particularly important aspects in the context of drug discovery pipelines. In this respect, nonequilibrium alchemical techniques have been shown to strike a good balance − and be a valid alternative to traditional equilibrium alchemical techniques (FEP), , while they are generally easier to automate than CV-based enhanced sampling algorithms, such as Metadynamics. , …”

“…One way to overcome this issue is to perform very long simulations to fully sample the slow degrees of freedom associated with long-lived waters and the repositioning of lateral chains, but this approach is extremely computationally demanding. On the shorter time scales that are routinely employed, it has been recently shown that carefully selected restraints between the protein and the ligand greatly help the convergence. However, the resulting binding affinities depend critically on the initial choice of binding pose, which determines the accuracy of the predictions. − …”

Accelerating and Automating the Free Energy Perturbation Absolute Binding Free Energy Calculation with the RED-E Function

“…In this work, we have mainly focused on the six-degree-of-freedom harmonic restraints, which are still widely used ,,− and also face several problems. (1) The restraint addition is typically based on the researcher’s understandings about the interaction between the receptor and the ligand, which is inconvenient for inexperienced researchers and difficult to handle a large number of ligands.…”