Proteins in their native folded states can possess multiple energy minima and they can show constant conformational fluctuations at physiological temperatures. In this article, we discuss the quantitative relationship between ligand-induced perturbation of such fluctuations, modeled as probability distributions of conformational substates, and allosteric coupling of ligand binding to different sites, as defined by linkage thermodynamics. We show that allosteric coupling between two binding events on the same protein is an inevitable consequence of ligand-induced perturbations of the probability distribution that represents conformational fluctuations in thermal equilibrium. When high resolution structural data of a protein in empty and ligand-bound forms are available, the COREX algorithm can provide, in principle, an excellent bridge between the energetics of substates distribution in the protein ensemble and structural coordinates. Here we propose a COREX-based strategic approach to link structural perturbations and the free energy changes of allosteric coupling. This strategy might be broadly useful in the endeavor of predicting how specific ligands allosterically regulate the function of specific proteins.