Aqueous Reaction Free Energy

Aqueous Reaction Free Energy calculates the free energy change of a chemical reaction happening in water, reported as a reaction free energy, ΔG_rxn, in kcal/mol. You give the reactants, the products, and how many of each take part (the stoichiometry).

A negative ΔG_rxn means the reaction is favorable in the forward direction (products are favored). A positive value means it is unfavorable, so reactants are favored.

Under the hood it computes the solvation free energy of every reactant and every product with alchemical free energy simulation, then combines them through a thermodynamic cycle to get the overall reaction free energy in water. You can optionally add a gas phase contribution computed with xTB, a fast quantum chemistry method, to capture the bond making and bond breaking part of the reaction.

When to use it

Use it when you want to know whether a reaction is thermodynamically favorable in water, or to compare the driving force of related reactions. Turn on use_xtb when the reaction changes which atoms are bonded together, since the water only calculation captures how the molecules interact with solvent but not the energy of forming or breaking bonds.

Inputs

Input	Required	What it is
`smiles_reactant`	yes	SMILES strings of the reactants, separated by commas.
`smiles_product`	yes	SMILES strings of the products, separated by commas.
`stoichiometry_reactant`	yes	How many of each reactant take part, separated by commas, in the same order as the reactants.
`stoichiometry_product`	yes	How many of each product form, separated by commas, in the same order as the products.
`solvent_equil_length`	no, default `0.08` ns	Equilibration length per replica, in water.
`solvent_prod_length`	no, default `0.4` ns	Production length per replica, in water.
`vacuum_equil_length`	no, default `0.08` ns	Equilibration length per replica, in vacuum.
`vacuum_prod_length`	no, default `0.4` ns	Production length per replica, in vacuum.
`platform`	no, default `CUDA`	Compute platform, one of `CUDA`, `OpenCL`, `CPU`, or `Reference`.
`protocol_repeats`	no, default `3`, minimum `1`	Number of independent repeats used for the uncertainty estimate. More repeats give a smaller uncertainty.
`use_xtb`	no, default `false`	Adds a gas phase free energy contribution computed with xTB. Turn on when the reaction breaks or forms bonds.
`keep_dirs`	no, default `true`	Preserves the full simulation outputs so you can download them.

Longer simulation lengths and more repeats give more reliable numbers, but cost more runtime and credits.

How to run it

Submit your own reaction from Azulene Studio, the Python SDK, or the CLI. New here? The Get started page walks through installing, logging in, and running a ready made example first.

In Azulene Studio

Open Aqueous Reaction Free Energy from the tools list, then on the Inputs and Parameters step enter the reactants and products as comma separated SMILES strings and their matching stoichiometry numbers, switch on xTB if your reaction changes bonds, adjust the simulation lengths if you want, then Review and Submit.

From the Python SDK

from opal import jobs

result = jobs.submit(
    job_type="reaction_free_energy",
    input_data={
        "smiles_reactant": "C(=O)=O,O",
        "smiles_product": "OC(=O)O",
        "stoichiometry_reactant": "1,1",
        "stoichiometry_product": "1",
        "use_xtb": True,
    },
)

From the CLI

Pass the inputs as a JSON string.

opal jobs submit --job-type reaction_free_energy \
  --input-data '{"smiles_reactant": "C(=O)=O,O", "smiles_product": "OC(=O)O", "stoichiometry_reactant": "1,1", "stoichiometry_product": "1", "use_xtb": true}'

Reading the result

The main output is dg_reaction, the reaction free energy ΔG_rxn in water, reported with an uncertainty, a dg_reaction_unit (kcal/mol), and an uncertainty_unit. In Azulene Studio this shows as a hero number labelled “ΔG reaction”. The reaction is echoed back in reactant_smiles and product_smiles.

When use_xtb is on, two extra fields appear: dg_reaction_gas, the gas phase reaction free energy from xTB (shown as a second hero number labelled “ΔG gas-phase (xTB)”), and dg_solvation_contribution, the part of the total that comes from how the molecules interact with water. A negative dg_reaction means the reaction is favorable in the forward direction. More protocol_repeats lower the uncertainty. If keep_dirs is on, the full simulation outputs can be downloaded.

Notes

Keep the simulation lengths short for a quick first run. For reliable numbers, use longer production lengths and at least 3 repeats. This tool runs on a GPU, and runtime grows with the simulation lengths and the number of repeats. The order of stoichiometry numbers must match the order of the SMILES strings on each side.