Conformational entropy is a potentially important thermodynamic parameter contributing to protein function. Quantitative measures of conformational entropy are necessary for an understanding of its role but have been difficult to obtain experimentally. We have recently introduced an empirical calibration method that utilizes the changes in conformational dynamics as a proxy for changes in conformational entropy. This approach raises several questions with regards to the microscopic origins of the measured conformational entropy as well as its general applicability. One of the goals in this work was to probe the microscopic origins of the link between conformational dynamics and conformational entropy. Using MD simulations, we find that the motions of methyl-bearing side chains are sufficiently coupled to that of other side chains and serve as excellently reporters of the overall side chain conformational entropy. We also propose a modified weighting scheme to project the change in NMR-measured methyl dynamics to conformational entropy. This approach has been extended to 36 different protein-ligand complexes each with different ligand types (small molecules, DNA/RNA, peptides and proteins) and binding affinities (10-4 to 10-14 M). There is excellent agreement between the NMR-measured conformational dynamics derived measure of conformational entropy and the total binding entropy, essentially postulating a 'Universal Entropy Meter'. This universal entropy meter can be utilized to measure the conformational entropy change for any protein-ligand interaction. The second major goal of this work is to understand the role played by conformational entropy in very high affinity interaction. A dominant view of very high affinity interactions involving proteins is that they are largely driven by both large favorable interactions at the interaction interface and by an increase in solvent entropy due to the creation of dry or solvent depleted interface. The role of conformational entropy, though admitted as a potentially favorable contribution, remains largely obscured by this view. Utilizing NMR measured conformational dynamics, protein conformational entropy was indeed found to play a pivotal role in achieving very high affinity interactions. In the barnase-barstar protein-protein complex (Kd = 10-14 M) and the histamine-binding protein bound to small molecule histamine (Kd = 2.5x10-9 M), large favorable changes in conformational entropy offset unfavorable entropic contributions from both solvent and rotational-translational contributions. Collectively, these results reveal that this mechanism involving modulation of protein conformational entropy changes to offset other entropic penalties could be a more prevalent paradigm for achieving high affinity interactions than previously anticipated.