Surface Plasmon Resonance (SPR) is an important bio-sensing technique for real-time labelfree detection. However, it is pivotal to optimize various parameters of the sensor configuration for efficient and highly sensitive sensing. To that effect, we focus on optimizing two different SPR structures-the basic Kretschmann configuration and narrow groove grating. Our analysis aims to detect two different types of lipids known as phospholipid and eggyolk, which are used as analyte (sensing layer) and two different types of proteins namely tryptophan and bovine serum albumin (BSA) are used as ligand (binding site). For both the configurations, we investigate all possible lipid-protein combinations to understand the effect of various parameters on sensitivity, minimum reflectivity and full width half maximum (FWHM). Lipids are the structural building block of cell membranes and mutation of these layers by virus and bacteria is one the prime reasons of many diseases in our body. Hence, improving the performance of a SPR sensor to detect very small change in lipid holds immense significance. We use finite-difference time-domain (FDTD) technique to perform quantitative analysis to get an optimized structure. We find that sensitivity increases when lipid concentration is increased and it is the highest (21.95 0 /RIU) for phospholipid and tryptophan combination when metal and lipid layer thickness are 45 nm and 30 nm respectively. However, metal layer thickness does not cause any significant variation in sensitivity, but as it increases to 50 nm, minimum reflectivity and full width half maximum (FWHM) decreases to the lowest. In case of narrow groove grating structure, broad range of wavelengths can generate SPR and the sensitivity is highest (900nm/RIU) for a configuration of 10 nm groove width and 70 nm groove height at a resonance wavelength of 1411 nm.