Bio-renewable resources have great potential to supersede conventional fossil fuel to meet energy and chemicals demands. Nevertheless, most of the processes employed for biomass conversion essentially requires the presence of an acid catalyst for sustainable production of fuel and chemicals. In this context, catalysts belonging to the family of Heteropolyacid (HPA) are extensively used owing to their excellent activity in biomass conversion reactions1. Albeit a wide range of HPA’s have been classified based on their geometrical arrangements, Keggin HPA’s represented by general formulae [XM12O40]n- have prevalence in industrial applications owing to their super acidic nature, high thermal stability at elevated temperatures in liquid phase reactions and ease of synthesis as compared to other HPA’s. In general, the central atom X can be either P, Si, Ge, B, or Al whereas the heteroatom M can be either W6+ or Mo6+ or V in which 12 linked octahedra containing addenda atoms (M12O36) surrounds a central tetrahedron (XO4n-). Interestingly, the higher activity of Keggin HPA’s is attributed to the combined effect arising from their stability, acidity, and structural accessibility, nevertheless no conclusive evidence has been suggested for the rational design of Keggin HPA’s. Moreover, the effect of changing central atom X on the activity of Keggin HPA’s is yet to be explored. Therefore, we have employed both theoretical and experimental approach to conclude deprotonation energy (DPE) as a suitable descriptor for rational design and selection of Keggin HPA’s. In this regard, Density functional theory (DFT) have been employed to calculate the DPE of known Keggin HPA’s with heteroatom W and Mo as well as propose the novel and futuristic catalysts by changing the central atom with elements from group 13-17 in the periodic table. Parallelly, esterification reactions have been performed with biomass-derived levulinic acid to produce additives for “green gasoline”2 in the presence of phosphotungstic acid and phosphomolybdic acid to validate the theoretical results. Interestingly, it was found that activity of Keggin HPA’s is a direct function of their DPE and difference in DPE remained constant when same elements from group 13-17 of the periodic table were put as central atom X in each of the Keggin HPA’s with W6+ and Mo6+ heteroatom. Nevertheless, change in the central atom of the Keggin HPA’s with W6+ and Mo6+ heteroatom caused a significant change in individual DPE’s, yet the overall difference in DPE remained constant when same central atoms were placed in both the catalysts. Interestingly, experimental results suggested similar trend and difference in activation barriers of both the catalysts with same central atom remained same even though esterification reactions were performed in different alcohols. Besides several tools and techniques such as XRD, BET, FT-IR, SEM, TEM, HPLC, GC-FID have been used for the characterization of catalysts and the product.