Protein-protein and protein-peptide interactions (PPIs and PPepI) belong to a similar category of interactions yet seemingly subtle differences exist among them. To characterize differences between protein-protein (PPI) and protein-peptide interactions (PPepI), we have focussed on two important class of residues- hotspot and anchor residues. Using implicit solvation-based free-energy calculations, a very large-scale alanine scanning has been performed on benchmarking dataset, consisting of over 5500 interface residues. The differences in the two categories are more pronounced, if the hotspot data is divided into three distinct types, namely - weak hotspots (having binding free energy loss upon Ala mutation, ΔΔG, 2-10 kcal/mol), moderate hotspots (ΔΔG, 10-20 kcal/mol) and strong hotspots (ΔΔG ≥ 20 kcal/mol). The analysis suggests that for PPI, weak hotspots are predominantly populated by polar and hydrophobic residues. The distribution shifts towards charged and polar residues for moderate hotspot and charged residues (principally Arg) are overwhelmingly present in the strong hotspot. In contrast, in the PPepI dataset, the distribution shifts from predominantly hydrophobic and polar (in the weak type) to almost similar preference for polar, hydrophobic and charged residues (in moderate type) and finally the charged residue (Arg) and Trp are mostly occupied in the strong type. In anchor residue class of both categories, the preferred residues are Arg, Tyr and Leu, possesing bulky side chaing and which also strike a delicate balance between side chain flexibility and rigidity. The present knowledge should aid in effective design of biologics, when augmentation or disruption of PPI are substituted with the peptide-based mimics.