Alchemical Transfer Approach to Absolute Binding Free Energy Estimation

Abstract

The alchemical transfer method (ATM) for the calculation of standard binding free energies of noncovalent molecular complexes is presented. The method is based on a coordinate displacement perturbation of the ligand between the receptor binding site and the explicit solvent bulk and a thermodynamic cycle connected by a symmetric intermediate in which the ligand interacts with the receptor and solvent environments with equal strength. While the approach is alchemical, the implementation of the ATM is as straightforward as that for physical pathway methods of binding. The method is applicable, in principle, with any force field, as it does not require splitting the alchemical transformations into electrostatic and nonelectrostatic steps, and it does not require soft-core pair potentials. We have implemented the ATM as a freely available and open-source plugin of the OpenMM molecular dynamics library. The method and its implementation are validated on the SAMPL6 SAMPLing host− guest benchmark set. The work paves the way to streamlined alchemical relative and absolute binding free energy implementations on many molecular simulation packages and with arbitrary energy functions including polarizable, quantum-mechanical, and artificial neural network potentials.

Developing end-point methods for absolute binding free energy calculation using the Boltzmann-quasiharmonic model

“…It is easy to see that first term in the right-hand side of eqn (18) is the uncorrelated first order Boltzmann entropy, i.e.…”

“…2s ii 2 . When the distributions p(q i ) are non-Gaussian, a more accurate treatment is to replace the first term in eqn (18) with the uncorrelated first order Boltzmann entropy…”

“…The receptor-ligand binding free energy can be computed using pathway methods such as the widely used alchemical pathway double decoupling method (DDM) [11][12][13] and physical pathway potential of mean force PMF 14 methods, and the more recently developed implicit ligand theory [15][16][17] and the alchemical transfer (ATM) method. 18 Alternatively, end-point methods such as MM-PB(GB)/SA, 19 LIE (Linear Interaction Energy), 20 and M2 (Mining Minima) 21 which need only consider the two end macrostates, are also popular in binding free energy calculations. While end-point methods generates a binding free energy estimate from the difference between two large numbers, which can lead to larger statistical error, such methods often allow for the binding free energy to be decomposed into physically intuitive components such as the direct intermolecular interaction, the solvation energy and entropy, and the solute configurational entropy, thus providing more direct insights into the thermodynamic driving forces of binding.…”

On the Consistency of the Exfoliation Free Energy of Graphenes by Molecular Simulations

“…We may configure various paths to transform state A into state B [ 30 , 31 ]. A common approach is to use a reaction coordinate to move reversibly from the A-like state to a B-like state.…”

Fast Equilibration of Water between Buried Sites and Bulk by MD with Parallel Monte Carlo Water Moves on GPUs

“…As a consequence, properly equilibrating water molecules is essential for attaining accurate results in MD simulations, such as calculating protein-ligand binding free energies with MDbased methods. [3][4][5][6] For example, alchemical methods that decouple the entire ligand from the binding site to compute absolute binding free energies, [7][8][9][10][11][12] or which chemically modify the ligand to compute relative binding free energies, [13][14][15][16][17] may not converge without accounting for resulting changes in the water occupancy of the binding site, especially for deeply buried cavities. 18 This is particularly problematic in drug discovery applications because the system may appear to be converged using standard MD analysis techniques, leading to false positive or false negative predictions.…”