Proteins are macromolecules that are called the “work horses” in the cell, as they play a crucial role in most life processes. The primary structure of a protein is made up of a linear chain of amino acids that are synthesized inside the cell through transcription and translation of the corresponding gene sequence. The functional protein is a three-dimensional (3-D) structure that forms due to folding of this linear chain based on the physicochemical forces exerted by the size, charge and chemical nature of the amino acids and their interaction with the environment. The 3-D structure consists of cavities (regions made up of multiple amino acids) for binding of the ligands and effector molecules, ions, DNA/RNA and even other proteins in a protein complex. Thus, the 3-D structure of the protein, which regulates the function of the protein, acts like a complex system whose emergent function depends on the composition and geometry of the constituent groups of amino acids that make up the functional region. Changes in the structure (due to mutation or chemical modification) induce alteration in its function—a feature known as the “structure-function paradigm” in structural biology. We have computationally modelled the 3-D structure of a protein using the network/graph theory, where the amino acids are the nodes/vertices and links/edges are the physicochemical forces/bonds that hold the atoms of any two amino acids close in the structure. We show how the network approach can be used to study the structure-function relationships in certain proteins (specifically, bacterial lipase A) and their mutants, which show insignificant variation in their 3-D conformation, but large changes in function (thermostability), which are not easily detectable using standard structural biology methods.