Amyloids, initially identified as anomalous sugar deposits in various tissues, including diseased brains, were subsequently revealed to be protein-based structures. Its specific structural characteristics were long shrouded in mystery until early X-ray diffraction studies on aggregated globulins provided hints of a distinctive design having intermolecular beta sheets oriented perpendicularly to the strand direction, forming the characteristic cross-β pattern seen in most amyloid structures. While amyloids have often been linked to various human diseases such as Alzheimer's and Parkinson's, it has become apparent that not only disease-related proteins adopt this structure. Surprisingly, many proteins can transition into the amyloid state under certain conditions, occasionally leading to new health-related issues. Recent advances have further expanded our understanding, revealing that numerous human proteins, even those unrelated to pathological conditions, can adopt a fibrillar amyloid-like organization, both in laboratory settings (in vitro) and within living organisms (in vivo). Among these proteins is glucagon, a peptide hormone composed of 29 amino acid residues in conjunction with insulin helps in regulating blood glucose level. This hormone is present in a wide variety of animals and is primarily synthesized in the pancreas, specifically by α cells. It hold a significant role in various metabolic pathways, influencing lipid metabolism, energy regulation, and amino acid metabolism. Irregularities in glucagon levels can contribute to various pathological conditions, including insulin resistance (linked to type-2 diabetes) and glucagonoma, which involves an elevated turnover of amino acids in the liver and irregular triglyceride breakdown. Though the exact biological functions of these glucagon fibrils have largely remained unexplored, it was suggested that amyloid fibrils as a group played a role in primitive catalytic reactions. This phenomenon was first demonstrated in synthetic amyloid-like systems. Recent experimental work has unveiled a catalytic potential of amyloid fibers formed by peptides like Alzheimer's disease peptide amyloid-β (Aβ) and glucagon, particularly when they take on a fibrillar form, unlike their monomeric counterparts. This finding suggests that the polymeric structure of amyloid fibers offers unique catalytic sites on their surface. Additionally, another independent research team has established that amyloid fibers formed by α-synuclein also exhibit enzyme-like catalytic properties in biological reactions. Collectively, these findings have indicated that naturally occurring amyloids can catalyze a range of physiological and pathological reactions, distinguishing them from synthetic, pre-designed amyloidogenic peptides. Given this emerging understanding, it encouraged us to delve into an atomistic examination of the catalytic mechanisms at play within the glucagon amyloid fibrils using QM/MM approaches.