Nonequilibrium Switching [MDRun] [FECalc]¶
Category Paths
Follow one of these paths in the Orion user interface, to find the floe.
Product-based/Molecular Dynamics/GROMACS
Role-based/Computational Chemist
Role-based/Medicinal Chemist
Task-based/Molecular Dynamics
Task-based/Affinity Prediction
Solution-based/Hit to Lead/Affinity Prediction/Free-Energy Calculations
Solution-based/Small Molecule Lead-opt/Affinity
Description
Tutorials and Further Reading:
Nonequilibrium Switching (to avoid leaving this page, right-click and open link in new tab)
Purpose:
This Floe performs relative binding free energy (RBFE) calculations using nonequilibrium switching (NES) method refined by the de Groot lab (Gapsys et al., Chem. Sci., 2020, 11, 1140-1152).
Method Recommendations/Requirements:
Four inputs are required:
An Orion dataset containing an equilibrium run for each bound ligand participating in the NES run.
An Orion dataset containing an equilibrium run for each unbound ligand participating in the NES run.
A Orion Dataset containing the ligand edges to run the RBFE calculation generated by using the Mapper Floe
[Optional] a text file containing experimental binding free energies for at least one ligand, one experimental datapoint per line, of form “ligA_name {deltaG(exptl)} {error_deltaG(exptl)} {units}” for example, “gn1c -8.56 0.17 kcal/mol”.
Limitations
If no experimental binding free energies (the fourth input above) are given, the estimation of ligand binding free energies has no reference value so the relative values will be centered around the mean.
Currently there is no mitigation for the effects of changes in buried waters, protein sidechain flips, or large protein movements between ligA and ligB.
Expertise Level:
Regular
Compute Resource:
High
Keywords:
MD, FECalc
Related Floes:
Ligand Bound and Unbound Equilibration for NES [MDPrep] [MD].
Equilibration and Nonequilibrium Switching [MDPrep] [MD] [FECalc].
Compare Experimental Affinity with NES Results [Utility] [FECalc].
Nonequilibrium Switching Recovery [Utility] [FECalc].
The Floe will draw a number of starting snapshots from the bound and unbound trajectories of the ligands. Then for each edge in the edge file, it will generate an RBFE alchemical transformation from ligA into ligB, and carry out the NES fast transformation of ligA into ligB, and vice versa, for each of the snapshots. The resulting relative free energy change, or DeltaDeltaG, for each edge is the primary output of this method. A maximum likelihood estimator is then used to derive a predicted binding affinity (free energy, or DeltaG) for each ligand. The mean value of the input experimental binding free energies is used as the reference value for the computed ones.
The speed of the NES transformation and the number of snapshots transformed can be adjusted from default values by the user at runtime. The Floe outputs two Floe report/dataset pairs, one for the calculated RBFE edges (DeltaDeltaGs), and one for the derived affinity predictions (DeltaGs) of ligand.
In free energy calculations, protein tumbling restraints are automatically applied if and only if they were requested and successfully applied in an upstream equilibrium simulation Floe that was used to generate input dataset for NES.
Promoted Parameters
Title in user interface (promoted name)
Optional parameters (promoted names)