Waheed Qaiser, Khan Hanif M, He Tao, Roberts Mary, Gershenson Anne, Reuter Nathalie
Department of Biological Sciences , University of Bergen , N-5020 Bergen , Norway.
Computational Biology Unit, Department of Informatics , University of Bergen , N-5020 Bergen , Norway.
J Phys Chem Lett. 2019 Jul 18;10(14):3972-3977. doi: 10.1021/acs.jpclett.9b01639. Epub 2019 Jul 3.
Membrane-binding interfaces of peripheral proteins are restricted to a small part of their exposed surface, so the ability to engage in strong selective interactions with membrane lipids at various depths in the interface, both below and above the phosphates, is an advantage. Driven by their hydrophobicity, aromatic amino acids preferentially partition into membrane interfaces, often below the phosphates, yet enthalpically favorable interactions with the lipid headgroups, above the phosphate plane, are likely to further stabilize high interfacial positions. Using free-energy perturbation, we calculate the energetic cost of alanine substitution for 11 interfacial aromatic amino acids from 3 peripheral proteins. We show that the involvement in cation-π interactions with the headgroups (i) increases the ΔΔ as compared with insertion at the same depth without cation-π stabilization and (ii) can contribute at least as much as deeper insertion below the phosphates, highlighting the multiple roles of aromatics in peripheral membrane protein affinity.
外周蛋白的膜结合界面局限于其暴露表面的一小部分，因此能够在界面的不同深度与膜脂进行强烈的选择性相互作用，无论是在磷酸基团下方还是上方，都是一个优势。受疏水性驱动，芳香族氨基酸优先分配到膜界面中，通常在磷酸基团下方，但与磷酸基团平面上方的脂质头部基团的焓有利相互作用可能会进一步稳定高界面位置。使用自由能微扰，我们计算了来自3种外周蛋白的11个界面芳香族氨基酸被丙氨酸取代的能量成本。我们表明，与在没有阳离子-π稳定作用的相同深度插入相比，参与与头部基团的阳离子-π相互作用（i）增加了ΔΔ，并且（ii）至少与在磷酸基团下方更深的插入一样重要，突出了芳香族在外周膜蛋白亲和力中的多种作用。
