The prion hypothesis states the misfolding of the prion protein in its normal isoform, PrPC, to an infectious isoform, PrPSc, is the foundational cause of transmissible spongiform encephalopathies. The oligomerization of PrPSc forms infectious amyloid fibers that prove to be neurotoxic, causing rapid onset of dementia and death. Although the etiology of the misfolding remains an enigma, current literature suggests the misfolding and aggregation of infectious prions are associated with specific lipids. In this work, we aim to assess the behavior of the PrPC in varied lipid compositions, primarily investigating the effect of sphingomyelin and phosphatidylglycerol lipids. In modeling protein behavior using molecular dynamics simulations, we ascertained how the normal prion isoform reacts to distinct lipid patches. From microsecond long trajectories, we quantified the behavior by measuring the angle of each α-helix and the distance of residues in reference to the lipid bilayer. Our numerical calculations of the PrPC bound to lipid membrane indicate the electrostatics between α-helical structures and membrane modulate the relative orientation of the PrPC. The patches that contain phosphatidylglycerol restrict the conformation of the PrPC that we extrapolate to be a susceptible orientation for catalyzing the misfolding of the non-infectious prion protein. We aim to discuss PrPC-lipid interactions critical for mechanistic misfolding and prion protein-fibril interactions.