Separated topologies—A method for relative binding free energy calculations using orientational restraints

Abstract

Orientational restraints can improve the efficiency of alchemical free energy calculations, but they are not typically applied in relative binding calculations, which compute the affinity difference been two ligands. Here, we describe a new "separated topologies" method, which computes relative binding free energies using orientational restraints and which has several advantages over existing methods. While standard approaches maintain the initial and final ligand in a shared orientation, the separated topologies approach allows the initial and final ligands to have distinct orientations. This avoids a slowly converging reorientation step in the calculation. The separated topologies approach can also be applied to determine the relative free energies of multiple orientations of the same ligand. We illustrate the approach by calculating the relative binding free energies of two compounds to an engineered site in Cytochrome C Peroxidase.

Calculating the Sensitivity and Robustness of Binding Free Energy Calculations to Force Field Parameters

“…15 and ref. 43. Protonation states of titratable residues were selected using MCCE 2.2 44,45 , with a reference pH of 4.5 for CCP (model 1KXN with the Heme removed) and pH 7.0 for Gyrase.…”

Is Ring Breaking Feasible in Relative Binding Free Energy Calculations?

“…These errors are limited to single-topology approach of the RBFE calculations, other methods like dual-topology approach 7–10 and separated-topology approach 11 should not suffer from these errors because they handle these transformations without introducing multiply-connected dummy atoms which interact with remaining atoms. But since the single topology approach is the default method for LOMAP and is widely used in RBFE calculations, these errors are still important.…”

Perspective: Alchemical free energy calculations for drug discovery

“…With a dual topology scheme, we can turn a ligand into dummy atoms in one binding mode while turning it on from dummy atoms in another, potentially using orientational restraints to ensure that no interconversion between binding modes happens during the calculations and thus obtaining a correct IFE. 107,108,129 Both of these approaches have the caveat that, as noted previously, treating different binding modes separately in the these calculations requires careful separation of kinetically distinct binding modes. 106,124 Consider a ligand L 1 which has two metastable binding modes A and B, and its transformation into L 2 which has the same two binding modes.…”

“…106,124 Relative calculations between binding modes seem likely to work particularly well, and would probably best be implemented with a dual topology strategy, where the ligand is turned off in one binding mode while being turned on in another binding mode. Orientational restraints 106 could be used to ensure the two binding modes are well separated and the correct IFE is obtained, as in Rocklin et al 129 Other potential strategies for computing IFEs include Markov state models, 124 metadynamics, and even the "deactivated morphing" approach. 130 We recommend one of two approaches to calculate the IFEs in a relatively general way, though more alternatives are becoming available:…”