CHARMM-GUI Free Energy Calculator for Absolute and Relative Ligand Solvation and Binding Free Energy Simulations

Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations

Binding selectivity is a requirement for the development of a safe drug, and it is a critical property for chemical probes used in preclinical target validation. Engineering selectivity adds considerable complexity to the rational design of new drugs, as it involves the optimization of multiple binding affinities. Computationally, the prediction of binding selectivity is a challenge, and genera...

Monte Carlo Free Ligand Diffusion with Markov State Model Analysis and Absolute Binding Free Energy Calculations.

Obtaining absolute binding free energies from unbiased ligand diffusion has attracted a significant amount of attention due to its implications in drug design. Several studies have used special purpose computers and software to achieve microsecond molecular dynamics which, combined with a Markov state model analysis, are capable of providing absolute binding free energies. We have recently deve...

Free energy calculations and ligand binding.

Enhanced Ligand Sampling for Relative Protein–Ligand Binding Free Energy Calculations

Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separati...

Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations.

The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallograph...