Lazaridis Themis, Leveritt John M, PeBenito Leo
Department of Chemistry, City College of New York, 160 Convent Avenue, New York, NY 10031, USA.
Department of Chemistry, City College of New York, 160 Convent Avenue, New York, NY 10031, USA.
Biochim Biophys Acta. 2014 Sep;1838(9):2149-59. doi: 10.1016/j.bbamem.2014.01.015. Epub 2014 Feb 10.
The energetic cost of burying charged groups in the hydrophobic core of lipid bilayers has been controversial, with simulations giving higher estimates than certain experiments. Implicit membrane approaches are usually deemed too simplistic for this problem. Here we challenge this view. The free energy of transfer of amino acid side chains from water to the membrane center predicted by IMM1 is reasonably close to all-atom free energy calculations. The shape of the free energy profile, however, for the charged side chains needs to be modified to reflect the all-atom simulation findings (IMM1-LF). Membrane thinning is treated by combining simulations at different membrane widths with an estimate of membrane deformation free energy from elasticity theory. This approach is first tested on the voltage sensor and the isolated S4 helix of potassium channels. The voltage sensor is stably inserted in a transmembrane orientation for both the original and the modified model. The transmembrane orientation of the isolated S4 helix is unstable in the original model, but a stable local minimum in IMM1-LF, slightly higher in energy than the interfacial orientation. Peptide translocation is addressed by mapping the effective energy of the peptide as a function of vertical position and tilt angle, which allows identification of minimum energy pathways and transition states. The barriers computed for the S4 helix and other experimentally studied peptides are low enough for an observable rate. Thus, computational results and experimental studies on the membrane burial of peptide charged groups appear to be consistent. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.
将带电基团埋入脂质双分子层疏水核心的能量成本一直存在争议，模拟结果给出的估计值高于某些实验结果。对于这个问题，隐式膜方法通常被认为过于简单。在此我们对这一观点提出质疑。IMM1预测的氨基酸侧链从水转移到膜中心的自由能与全原子自由能计算结果相当接近。然而，对于带电侧链，自由能分布的形状需要修改以反映全原子模拟结果（IMM1-LF）。通过将不同膜宽度下的模拟与弹性理论估算的膜变形自由能相结合来处理膜变薄问题。该方法首先在电压传感器和钾通道的孤立S4螺旋上进行测试。对于原始模型和修改后的模型，电压传感器都以跨膜方向稳定插入。在原始模型中，孤立S4螺旋的跨膜方向不稳定，但在IMM1-LF中有一个稳定的局部最小值，能量略高于界面方向。通过绘制肽的有效能量作为垂直位置和倾斜角的函数来解决肽的转运问题，这有助于识别最低能量路径和过渡态。为S4螺旋和其他实验研究的肽计算出的势垒足够低，能够观察到速率。因此，关于肽带电基团膜埋藏的计算结果和实验研究似乎是一致的。本文是名为：界面活性肽和蛋白质的特刊的一部分。客座编辑：威廉·C·温姆利和卡利娜·赫里斯托娃。
