Amphiphilic derivative of the laminin peptide YIGSR and three other mutated peptides with mutation at Y with V (valine), I (isoleucine), and L (leucine) have been synthesized. The monolayer formation and the stability of these peptide analogues at air/water interface and the interaction with phospholipid monolayers have been studied using surface pressure-molecular area (pi-A) and surface potential-molecular area (DeltaV-A) isotherms. The single amino acid mutation in the native sequence leads to appreciable changes in surface activity, orientation and insertion into lipid monolayers with LIGSR showing most hydrophobic character while YIGSR showed most polar nature. The morphology of spread monolayers in the most close packed state was carried out using Brewster angle microscopy (BAM). LB films of these amphiphilic peptide derivatives transferred to hydrophilic quartz surfaces and hydrophobically modified surfaces showed significant changes in the work of adhesion as well as spreading behavior of water with the L substituted sequence showing maximum work of adhesion and the native sequence YIGSR, the least work of adhesion. From theoretical estimates, the long-range effects of the different amino acid residues in position 1 on the alkyl chains have been studied from charge on the carbon and hydrogen atoms of the alkyl tails. The present study demonstrates that amphiphilic derivatives of the laminin peptide YIGSR show enhanced activity compared to the original sequence. This work shows that the amino acid substituents on the head group clearly influence the distal methylene groups of the tail. Thus, any mutation of even single amino acid in a peptide sequence influences and plays an important role in determining macroscopic properties such as surface energy and adhesion both at air/solution and solid/solution interfaces.