HYDROCARBON PERMEATION THROUGH LIPID BILAYERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 动机：了解分子穿透细胞膜的机制对于深入了解许多生物过程非常重要，例如药物输送和毒性。虽然通过脂质双层(模拟细胞膜)的渗透已经得到了广泛的研究，但对渗透的潜在热力学贡献还没有被很好地理解1，2。这个项目的目标是使用先进的分子模拟方法和高性能计算来获得关于人和脂双层之间的生物物理的详细知识。建议的研究：多环芳烃(PAH)广泛存在于环境中，具有毒性和致癌性，但其毒性机制尚不清楚3，4。已知多环芳烃与生物膜相互作用，由此引起的膜结构和功能的变化可能会损害细胞的生长和活性。在这个项目中，我们将利用分子动力学(MD)方法研究一系列含有6到20个碳原子的多环芳烃在脂质双层中的传输。这项研究的主要目的是以系统的方式深入了解大小和形状对脂质双层渗透的影响，这在文献中还没有得到充分的证明。自由能方法：从分子动力学模拟中计算自由能的一些方法已经开发出来，并在文献中使用。其中一些最常用的方法包括自由能微扰法(FEP)、热力学积分法(TI)、加权直方图分析伞形抽样(US-WHAM)和约束力(CF)5。由于膜的不均匀性，采样将沿着平行于双层法线6的反应坐标进行。在文献中，CF和US-WHAM方法都被成功地用于确定通过双层的平均力(PMF)势。这些方法之间的主要区别之一是US-WHAM计算特定相空间窗口中的状态密度，而CMF计算来自周围系统的粒子的平均作用力。力平均通常提供更好的状态收敛密度，因此我将使用CF方法来寻找PMF6。Cf还可以更轻松地促进并行模拟。与CF方法一起，TI方法将被用来计算双层中几个离散点之间的自由能差以及在不同温度下的自由能差。然后，来自TI方法的结果将被用于验证CF模拟并确定自由能的分量7。高性能计算：该项目是利用高性能计算资源的理想选择。在单个处理器上进行每一次模拟都需要几个月的时间，但如果并行执行，挂钟时间可以缩短到几周。除了模拟所需的计算时间外，还需要大量数据来计算有意义的PMF。对于正己烷渗透二油酰磷脂酰胆碱模型膜的体系，产生PMF8总共需要500 ns的模拟时间。在单个处理器上，该模拟可能需要一年多的时间才能完成，并且具有两个飞秒的时间步长，将需要存储多达2500万个时间步长的数据。这些要求只适用于产生一个分子的PMF。时间线CF模拟：1-4个月计算PMF：4-6个月TI模拟：6-8个月不同温度下的TI：9-12个月参考：1)柯鹏华，乔荣杰物理。凝聚态物质。19：(2007)2)Ginzberg V.V.，Balijepalli S.Nano Letters。首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容化学。262(6)：2514(1986)；4)Bemporad D.，Luttmann C.，Essex J.W.生物物理。J.87：1(2004)；5)Ghoufi A.，Malfreyt P.Molec。太棒了。104(22-24)：3787(2006)；6)Trzesniak D.，Kunz A.E.，van Gunsteren W.F.ChemPhysChem.8：162(2007)；7)彼得·C，奥斯滕布林克·C，范·多普·A，范·冈斯特伦W.F.J.化学。太棒了。120(6)：2653(2004)；8)MacCallum J.L.，Tieleman D.P.J.Am化学。SoC。128：125(2005)

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Motivation: Understanding the mechanisms through which molecules penetrate cell membranes is important for gaining insight into many biological processes such as drug delivery and toxicity. While permeation through lipid bilayers, which model cell membranes, has been studied extensively, the underlying thermodynamic contributions to penetration are not well understood1,2. The goal of this project is to gain detailed knowledge of the biophysics between a permeant and lipid bilayer using advanced molecular modeling methods and high performance computing. Proposed Reasearch: Polycyclic Aromatic Hydrocarbons (PAH) are widespread in the environment and are well known to be toxic and carcinogenic but mechanisms for their toxicity are not clear3,4. It is known that PAH interact with biological membranes, and it is suspected that resulting changes to the structure and functioning of the membrane impair cell growth and activity3. In this project we will study the transport of a series of PAH containing from six to twenty carbon atoms, in lipid bilayers to gain using molecular dynamic (MD) approaches. The main objective of the study is to gain insights into effects of size and shape on permeation of a lipid bilayer in a systematic way that has not been adequately shown in literature. Free Energy Methods: A number of methods for calculating free energies from MD simulations have been developed and used in literature. Some of the most used of these methods include free energy perturbation (FEP), thermodynamic integration (TI), umbrella sampling with the weighted histogram analysis method (US-WHAM), and constraint force (CF)5. Due to the inhomogeneity of the membrane, the sampling will be carried out along a reaction coordinate parallel to the bilayer normal6. Both CF and US-WHAM methods have been successfully used in literature for determining a potential of mean force (PMF) through a bilayer. One of the major differences between these methods is that US-WHAM counts the density of states in a particular phase space window whereas CMF averages forces on a particle from the surrounding system. Force averaging generally provides better convergence density of states therefore I will use the CF method to find the PMF6. CF also more easily facilitates parallel simulations. Together with the CF method, the TI approach will be used to calculate the free energy differences between a few discrete points in the bilayer as well as at various temperatures. The results from the TI method will be then used to validate the CF simulations and determine components of the free energy7. High-performance Computing: This project is ideal for utilizing high-performance computational resources. Each of these simulations would take months on a single processor but, when performed in parallel, the wall clock time could be shortened to weeks. In addition to the computational time required for the simulations, large amounts of data are needed to calculate a meaningful PMF. For a system composed of hexane permeating a dioleoyl phosphatidylcholine model membrane, a total of 500ns of simulation time was required for generating the PMF8. On a single processor that simulation could take over a year to complete and with a two femtosecond time step, would require storage of data for up to twenty-five million time steps. These requirement are for generating the PMF of one molecule only. Timeline CF simulations: Months 1-4 calculating PMF: Months 4-6 TI simulations: Months 6-8 TI at various temperatures: Months 9-12 References: 1) Ke P.C., Qiao R. J. Phys. Condensed Matter. 19: (2007) 2) Ginzberg V.V., Balijepalli S. Nano Letters. 0 (0): (2007); 3) Plant A.L., Knapp R.D., Smith L.C. J. Biol. Chem. 262 (6): 2514 (1986); 4) Bemporad D., Luttmann C., Essex J.W. Biophys. J. 87: 1 (2004); 5) Ghoufi A., Malfreyt P. Molec. Phys. 104 (22-24): 3787 (2006); 6) Trzesniak D., Kunz A.E., van Gunsteren W.F. ChemPhysChem. 8: 162 (2007); 7) Peter C., Oostenbrink C., van Dorp A., van Gunsteren W.F. J. Chem. Phys. 120 (6): 2653 (2004); 8) MacCallum J.L., Tieleman D.P. J. Am. Chem. Soc. 128: 125 (2005)