Allostery in proteins is key to understand the mechanism of diverse processes. A ligand binding induced allostery is a very broad subject of study and molecular simulations are fundamental to gain details. Here we will focus on how allostery is connected with transport phenomena with two examples from prokaryotic and eukaryotic cells. One of the challenge of modern medicine is to find efficient antibiotics to counteract infections, especially caused by Gram negative species. These bacteria possess an additional outer membrane that prevents the entry of molecules. A possible approach is to use TonB dependent transporters, such as those expressed to capture iron from the environment, modifying existing siderophore molecules. These Trojan-Horse candidates, enriched by anti-infective properties, can be efficiently transported inside the cell. The knowledge we have is based on few co-complexes of natural siderophores with their receptors. Starting from these co-complexes, we proved that upon binding a unique allosteric signal appears to activate other regions of the transporters in order to control the self-transport of the ligand, as verified with all-atom metadynamics simulations. Another thrilling effect of the ligand binding is observed in another family of membrane proteins, the sodium selective two-pore channels (TPCs), that has an interesting dimeric architecture. In TPC1 from mammalian cells, the translocation of sodium is controlled by several factors among which is binding of the PtdIns(3,5)P2(PIP) and application of voltage. In our simulations we have observed the strong correlation induction between the two TPC units in the presence of the PIP molecule. This allosteric interaction is able to couple the gate region with voltage sensing domains (VSDs). Thus, our analysis suggests the correlation is voltage sensitive and controls through the gate the flux of sodium ions.

Allosteric transport in ion channels and receptors

2019 Fall National Meeting

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