Free energy differences between λ = 1 and λ = 0 states can be estimated using a variety of methods such as umbrella sampling, thermodynamic integration, and nonequilibrium work methods. Alchemical approaches have been used to calculate free energy differences between protonated and deprotonated states and are commonly used to calculate free energies of binding. This approach has also been used in the λ -dynamics method, where each λ is considered as a dynamical variable. That is, λ feels a force according to: F λ = -∂U/∂ λ , and has a velocity v λ and a mass m λ . The λ -dynamics method has been successfully applied to calculations of hydration free energies, binding free energies and to sample ligand binding modes. To enable the continuous and dynamic description of chemical identities in the Flexible Topology method, we separate external interactions from internal ones and treat them separately. While internal interactions are complex and involve a multitude of atom-type specific parameters, external interactions are comprised of only Lennard-Jones and electrostatic interactions that can be wholly described by only three parameters: partial charges (q), Lennard-Jones well-depths (ε) and Lennard-Jones radii (σ ). In Flexible Topology, each atom is assigned a dynamic λ variable, as well as three parameters q i , ε i , and σ i . These are all treated as dynamical variables that change as a function of time and together we refer to them as "attributes" denoted by A i = {q i , ε i , σ i , λ i } for atom i and A GP for the complete set. These variables, like λ , have masses (m q , m ε and m σ ) and their motion follows the gradients of an extended Hamiltonian energy function. These dynamic variables are used to model non-bonded interactions of the shape-shifting ligand atoms, which we refer to as "ghost particles", using conventional Lennard-Jones and Coulomb equations. The ghost particle positions and attributes both change together over the course of a trajectory and are influenced both by their surrounding environment and symmetry-invariant restraint terms that encourage the particles to assemble to one or more target molecular structures. Importantly, the environment -binding site residues and water molecules -can in turn respond to the presence of the ghost particles, providing a mechanism to model ligand-induced conformational change.