Kessel Amit, Tieleman D Peter, Ben-Tal Nir
Department of Biochemistry, George S Wise Faculty of Life Sciences, Tel Aviv University, 69978, Ramat Aviv, Israel.
Eur Biophys J. 2004 Feb;33(1):16-28. doi: 10.1007/s00249-003-0345-4. Epub 2003 Sep 17.
Alamethicin is a hydrophobic helical peptide of 20 residues, which oligomerizes to form ion-conducting channels in membranes. The behavior of an intact alamethicin channel in POPC bilayers was recently studied, using 2 ns molecular dynamics (MD) simulations of a model hexameric channel. These simulations produced numerous conformations of the channel. In the present study, we used 11 of these channel conformations and carried out continuum-solvent model calculations, similar to those used for the monomers in our previous studies, to investigate the energetics of the channel inside the lipid bilayer. Our results suggest that, out of the 11 channel conformations produced by the MD simulations, only four are stable inside the lipid bilayer, with water-to-membrane free energies of transfer ranging from approximately -6 to approximately -10 kcal/mol. Analysis of the results suggests two causes for the apparent instability of the remainder of the structures inside the lipid bilayer, both resulting from the desolvation of channel polar groups (i.e. their transfer from the aqueous phase into the bilayer). The first is specific, uncompensated backbone hydrogen bonds, which exist in the region of the channel exposed to the hydrocarbon of the lipid bilayer. The second is exposure of intra-pore water molecules to the surrounding lipid. Thus, the association of these structures with the membrane involves a large electrostatic desolvation free-energy penalty. The apparent conflict between continuum-solvent and MD calculations, and its significance for the interpretation of membrane proteins simulations, are discussed.
阿拉霉素是一种由20个残基组成的疏水性螺旋肽，它会寡聚形成膜中的离子传导通道。最近，通过对一个模型六聚体通道进行2纳秒的分子动力学（MD）模拟，研究了完整的阿拉霉素通道在POPC双层膜中的行为。这些模拟产生了通道的众多构象。在本研究中，我们使用了其中11种通道构象，并进行了连续溶剂模型计算，类似于我们之前研究中对单体所使用的计算，以研究脂质双层内部通道的能量学。我们的结果表明，在MD模拟产生的11种通道构象中，只有四种在脂质双层内部是稳定的，水到膜的转移自由能范围约为 -6至约 -10千卡/摩尔。对结果的分析表明，脂质双层内部其余结构明显不稳定有两个原因，均源于通道极性基团的去溶剂化（即它们从水相转移到双层膜中）。第一个原因是特定的、未得到补偿的主链氢键，其存在于通道暴露于脂质双层烃类的区域。第二个原因是孔内水分子暴露于周围脂质中。因此，这些结构与膜的结合涉及很大的静电去溶剂化自由能惩罚。讨论了连续溶剂计算和MD计算之间明显的冲突及其对膜蛋白模拟解释的意义。
