Here, polar solute...amphiphile interactions are hypothesized to collectively control the amphiphile conformational distribution and modulate the underlying PEL. A workflow is developed for Markov state modelling that investigates the large pool of conformations that arise from the breadth of amphiphiles present in MD simulation; the MSM is used to explain the important changes to the topology of the PEL that results from solute-solvent interactions. The specific system under study consists of the well-known amphiphile extractant N,N,N ′ ,N ′ -tetraoctyl diglycolamide (TODGA). TODGA is used as a general extractant of many metals and is notable for its use in the ALSEP process of solvent extraction in the separation of spent nuclear fuel. A solution consisting of 0.1 M TODGA forms reversemicelle like aggregates in n-dodecane mixtures with 0.2 M [H 2 O] and 0.15 M [HNO 3 ]. Benchmarked molecular dynamics simulation followed by MSM analysis clearly articulates that the change in solvation environment caused by polar solutes has an immediate impact over the distribution of stable TODGA conformations in phase-space. Subsequent welltempered metadynamics simulations further indicate that the polar solute modulates the the free energy barrier of conformational transitions about key TODGA dihedral angles.