Interaction of the Immune System TIM‐3 Protein with a Model Cellular Membrane Containing Phosphatidyl‐Serine Lipids

Abstract

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.

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“…49 Recently, by using enhanced sampling and extended Molecular Dynamics (MD) simulations the thermodynamic parameters of the interaction between the IvG domain and PDS containing lipids have also been determined. 16 Notably, we have shown that the inclusion of the lipid in the binding pocket is barrierless and favored by a free energy driving force of about 15-20 kcal/mol. 16 While the polar head is held tight between the FG and CC' loops, the lipid tails remain globally parallel to the membrane axis and stretch away from the IvG surface.…”

“…16 Notably, we have shown that the inclusion of the lipid in the binding pocket is barrierless and favored by a free energy driving force of about 15-20 kcal/mol. 16 While the polar head is held tight between the FG and CC' loops, the lipid tails remain globally parallel to the membrane axis and stretch away from the IvG surface.…”

“…A mixture of lipids, including POPC, POPE, POPS, and cholesterol, was used with respective molar ratios of 30%, 25%, 15%, and 30%, placing a total of 200 lipids in each leaflet, in coherence with the strategy used in our previous work. 59 A 30 Å water buffer containing a physiological concentration of 0.15 M and K + and Clions was also included and added to the system. The IgV domain of murine TIM-3 protein, sourced from the PDB database (PDB: 3KAA), 60 provided the starting protein's conformation.…”

“…To place one PSL lipid in the IvG binding site we used a similar strategy to the one applied in our previous work. 59 Concretely, we considered IvG in interaction with a native POPS lipid extracted after 1 μs MD simulation. Since the polar head of the native lipid (phosphatidylserine) is identical to the one of PSL, we aligned the latter, either in E-or Z-conformation, with the POPS lipid using the VMD program to obtain the two starting conformations for the MD simulations involving either E-or Z-PSL.…”

“…In the case of TIM-1, TIM-3, and TIM-4 receptors, the IgV domain senses the external lipid leaflet of other cellular membranes (Figure 1B) and interacts specifically with lipids whose polar head contains phosphatidylserine (PDS) moieties. 12,[15][16][17][18][19] This specificity is at the base of their action, characterizing them as efficient sensors of apoptotic cells [20][21][22][23][24][25][26][27][28] since that during apoptosis PDS-containing lipids migrate from the inner to the outer leaflet of the cellular membrane. 22 In contrast with the other members of the family, TIM-2 does not interact with PDS and should, thus, be related to a different mechanism of actions, which remains elusive to date.…”