Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York 10065, United States.
J Phys Chem B. 2011 Jun 9;115(22):7417-26. doi: 10.1021/jp200904d. Epub 2011 May 16.
Gramicidin A (gA) channels provide an ideal system to test molecular dynamics (MD) simulations of membrane proteins. The peptide backbone lines a cation-selective pore, and due to the small channel size, the average structure and extent of fluctuations of all atoms in the peptide will influence ion permeation. This raises the question of how well molecular mechanical force fields used in MD simulations and potential of mean force (PMF) calculations can predict structure and dynamics as well as ion permeation. To address this question, we undertook a comparative study of nuclear magnetic resonance (NMR) observables predicted by fully atomistic MD simulations on a gA dimer embedded in a sodium dodecyl sulfate (SDS) micelle with measurements of the gA dimer backbone and tryptophan side chain dynamics using solution-state (15)N NMR on gA dimers in SDS micelles (Vostrikov, V. V.; Gu, H.; Ingólfsson, H. I.; Hinton, J. F.; Andersen, O. S.; Roux, B.; Koeppe, R. E., II. J. Phys. Chem. B2011, DOI 10.1021/jp200906y , accompanying article). This comparison enables us to examine the robustness of the MD simulations done using different force fields as well as their ability to predict important features of the gA channel. We find that MD is able to predict NMR observables, including the generalized order parameters (S(2)), the (15)N spin-lattice (T(1)) and spin-spin (T(2)) relaxation times, and the (1)H-(15)N nuclear Overhauser effect (NOE), with remarkable accuracy. To examine further how differences in the force fields can affect the channel conductance, we calculated the PMF for K(+) and Na(+) permeation through a gA channel in a dimyristoylphosphatidylcholine (DMPC) bilayer. In this case, we find that MD is less successful in quantitatively predicting the single-channel conductance.
短杆菌肽 A（gA）通道为测试膜蛋白的分子动力学（MD）模拟提供了理想的系统。该肽的肽骨架排列在阳离子选择性孔中，由于通道尺寸较小，因此肽中所有原子的平均结构和波动程度都会影响离子渗透。这就提出了一个问题，即 MD 模拟中使用的分子力学力场以及平均势（PMF）计算在预测结构和动力学以及离子渗透方面的效果如何。为了解决这个问题，我们对嵌入十二烷基硫酸钠（SDS）胶束中的 gA 二聚体进行了全原子 MD 模拟的核磁共振（NMR）观测值进行了比较研究，并使用 SDS 胶束中的 gA 二聚体的溶液态（15）N NMR 测量了 gA 二聚体的骨架和色氨酸侧链动力学（Vostrikov，VV；Gu，H；Ingólfsson，HI；Hinton，JF；Andersen，OS；Roux，B；Koeppe，RE，II。J. Phys. Chem. B2011，DOI 10.1021/jp200906y ，伴随文章）。这种比较使我们能够检查使用不同力场进行的 MD 模拟的稳健性及其预测 gA 通道重要特征的能力。我们发现 MD 能够以惊人的精度预测 NMR 观测值，包括广义序参数（S（2）），（15）N 自旋晶格（T（1））和自旋-自旋（T（2））弛豫时间以及（1）H-（15）N 核奥弗豪瑟效应（NOE）。为了进一步检查力场的差异如何影响通道电导，我们计算了通过二肉豆蔻酰磷脂酰胆碱（DMPC）双层的 gA 通道中 K（+）和 Na（+）渗透的 PMF。在这种情况下，我们发现 MD 在定量预测单通道电导方面的效果较差。
