Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94550, United States.
Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
J Chem Theory Comput. 2021 Jan 12;17(1):7-12. doi: 10.1021/acs.jctc.0c00989. Epub 2020 Dec 30.
We investigated gramicidin A (gA) subunit dimerization in lipid bilayers using microsecond-long replica-exchange umbrella sampling simulations, millisecond-long unbiased molecular dynamics simulations, and machine learning. Our simulations led to a dimer structure that is indistinguishable from the experimentally determined gA channel structures, with the two gA subunits joined by six hydrogen bonds (6HB). The simulations also uncovered two additional dimer structures, with different gA-gA stacking orientations that were stabilized by four or two hydrogen bonds (4HB or 2HB). When examining the temporal evolution of the dimerization, we found that two bilayer-inserted gA subunits can form the 6HB dimer directly, with no discernible intermediate states, as well as through paths that involve the 2HB and 4HB dimers.
我们使用微秒级别的 replica-exchange umbrella sampling 模拟、毫秒级别的无偏分子动力学模拟和机器学习研究了革兰氏杀菌素 A（gA）亚基在脂质双层中的二聚化。我们的模拟得到了一个二聚体结构，与实验确定的 gA 通道结构无法区分，两个 gA 亚基通过六个氢键（6HB）连接。模拟还揭示了另外两种二聚体结构，它们具有不同的 gA-gA 堆积取向，由四个或两个氢键（4HB 或 2HB）稳定。在研究二聚化的时间演化时，我们发现两个插入双层的 gA 亚基可以直接形成 6HB 二聚体，没有明显的中间状态，也可以通过涉及 2HB 和 4HB 二聚体的途径形成。
