The biological membrane is necessary for maintaining cellular identity, yet must also allow for interaction with the extracellular environment in order to respond to stimuli. Proteins that are directly embedded in the membrane or that interact more peripherally are responsible for these extracellular signaling events, which lie at the heart of cell communication. The first major goal of this work was to interrogate the peripheral interaction of cytochrome c and the mitochondrial lipid cardiolipin at atomic resolution using solution nuclear magnetic resonance (NMR) techniques; this interaction is key to promoting apoptosis. After demonstrating that the protein was correctly folded in the reverse micelle solution used as a membrane mimetic, cardiolipin was introduced to confirm two previously predicted sites of interaction as well as to identify and propose a novel third site. Next, NMR-derived methyl side chain order parameters have been shown to be important in the thermodynamics of intermolecular interactions. Molecular simulation has become routine in investigations of protein dynamics with atomic-level information, yet their accuracy in replicating experimental dynamics measurements is unknown. Using a variety of standard “force-fields”, it becomes apparent that both common implementations perform comparably, yet outside of the model ubiquitin system, much progress remains in this area. Simulations were then used to interrogate the role of backbone motions in protein thermodynamics. Finally, though we now know much about the role of methyl dynamics in protein conformational entropy, this view has been attained solely with soluble protein systems; the dynamic behavior of membrane proteins remains to be elucidated. Utilizing a newly designed labeling technique for producing deuterated, appropriately methyl-labeled samples, we collected the first quantitative side chain dynamics experiments on several large, integral membrane protein systems. These experiments revealed that membrane proteins apparently contain massive wells of residual conformational entropy, manifested in the extremely dynamic average behavior of the side chain methyl groups. This extraordinary average behavior is the result of the emergence of a previously unobserved “hyper-dynamic” band of methyl groups that explore extensive amounts of rotameric space. In contrast, a series of structural waters and buried polar residues are very rigid by simulation and appear necessary for maintaining a single tertiary structure.