Method to calculate free energies

A method of calculating a difference in free-energy at molecular level, the method comprising:

• computationally transforming, by a computer, a first molecule into a first replica molecule being similar to the first molecule, and a second molecule into a second replica molecule being similar to the second molecule;
• separately calculating, by said computer, a difference in free-energy between said first molecule and said first replica molecule at an environment, and a difference in free-energy between said second molecule and said second replica molecule at said environment;
• and
• based on said calculated differences, calculating, by said computer, a total free-energy difference between said first and said second molecules at said environment.

A method of calculating a difference in free-energy at molecular level, the method comprising:

• computationally transforming, by a computer, a first molecule into a first replica molecule being similar to the first molecule, and a second molecule into a second replica molecule being similar to the second molecule, wherein the potential terms of the replicas are determined based on the potential terms of the two molecules;
• for each environment of a first environment and a second environment, separately calculating, by said computer, a difference in free-energy between said first molecule and said first replica molecule at said environment, and a difference in free-energy between said second molecule and said second replica molecule at said environment;
• and
• based on said calculated differences, calculating, by said computer, a total free-energy difference between an interaction process when involving said first molecule and said interaction process when involving said second molecule.

A method of calculating free-energy of a molecular model describing a molecule, the method comprising:

• removing, by a computer, coupling terms from the molecular model, thereby providing a similar replica molecule having a plurality of sub-systems;
• calculating, by said computer, a difference in free-energy between the molecule and said replica;
• independently calculating, by said computer, a free-energy value for each of said sub-systems thereby providing a plurality of free-energy values, by computing for said subsystem at least one statistical partition function selected from the group consisting of:
• a statistical partition function describing uncoupling bonded terms in said sub-system, a statistical partition function describing non-quadratic uncoupling bonded terms in said sub-system, a statistical partition function describing bond junctions in said sub-system and a statistical partition function describing a complex structure in said sub-system;
• and
• based on said difference in free-energy and said free-energy values, calculating, by said computer, the free-energy of the molecular model.