T cell transmembrane, Immunoglobulin, and Mucin (TIM) are important immune system proteins which are especially present in T‐cells and regulated the immune system by sensing cell engulfment and apoptotic processes. Their role is exerted by the capacity to detect the presence of phosphatidyl‐serine lipid polar head in the outer leaflet of cellular membranes (correlated with apoptosis). In this contribution by using equilibrium and enhanced sampling molecular dynamics simulation we unravel the molecular bases and the thermodynamics of TIM, and in particular TIM‐3, interaction with phosphatidyl serine in a lipid bilayer. Since TIM‐3 deregulation is an important factor of pro‐oncogenic tumor micro‐environment understanding its functioning at a molecular level may pave the way to the development of original immunotherapeutic approaches.