An implicit membrane generalized born theory for the study of structure, stability, and interactions of membrane proteins
An implicit membrane generalized born theory for the study of structure, stability, and interactions of membrane proteins
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DOI：
10.1016/s0006-3495(03)74712-2
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发表时间：
2003-11-01
影响因子：
3.4
通讯作者：
Brooks, CL
中科院分区：
文献类型：
--
作者：
Im, W;Feig, M;Brooks, CL
利用最近的发展，广义玻恩（GB）静电理论，我们已经重新制定了计算的自静电溶剂化能占生物膜的影响。与连续泊松-玻尔兹曼（PB）静电学一致，膜近似为溶剂不可及的无限平面低介电板。本膜GB模型密切再现PB的静电溶剂化能分布在整个膜。溶剂化能的非极性贡献被认为是成比例的溶剂暴露的表面积（SA）与现象学的表面张力系数。拟议的膜GB/SA模型需要对现有的GB模型进行微小修改，并且似乎非常有效。通过结合这种隐式模型的溶剂/双层环境与先进的计算采样方法，如复制交换分子动力学，我们能够折叠和组装螺旋膜肽。我们研究的可靠性，这个模型和方法的应用程序的三个膜肽：蜂毒肽从蜂毒，跨膜结构域的M2蛋白从流感A（M2-TMP），和跨膜结构域的血型糖蛋白A（GpA）。在这些蛋白质的背景下，我们探索生物膜（表示为低介电介质）在影响蜂毒肽的构象变化，跨膜肽相对于膜正常（M2-TMP），螺旋-螺旋相互作用的膜（GpA），和跨膜螺旋束（GpA）的配置预测的倾斜的作用。发现本方法在这些情况下的每一个中表现良好，并且预期在膜蛋白的折叠和组装的研究中以及在膜蛋白的结构细化和建模中是有用的，其中有限数量的实验观测值是可用的。
Exploiting recent developments in generalized Born ( GB) electrostatics theory, we have reformulated the calculation of the self-electrostatic solvation energy to account for the influence of biological membranes. Consistent with continuum Poisson-Boltzmann (PB) electrostatics, the membrane is approximated as an solvent-inaccessible infinite planar low-dielectric slab. The present membrane GB model closely reproduces the PB electrostatic solvation energy profile across the membrane. The nonpolar contribution to the solvation energy is taken to be proportional to the solvent-exposed surface area (SA) with a phenomenological surface tension coefficient. The proposed membrane GB/SA model requires minor modifications of the pre-existing GB model and appears to be quite efficient. By combining this implicit model for the solvent/ bilayer environment with advanced computational sampling methods, like replica-exchange molecular dynamics, we are able to fold and assemble helical membrane peptides. We examine the reliability of this model and approach by applications to three membrane peptides: melittin from bee venom, the transmembrane domain of the M2 protein from Influenza A (M2-TMP), and the transmembrane domain of glycophorin A (GpA). In the context of these proteins, we explore the role of biological membranes (represented as a low-dielectric medium) in affecting the conformational changes in melittin, the tilt of transmembrane peptides with respect to the membrane normal (M2-TMP), helix-to-helix interactions in membranes ( GpA), and the prediction of the configuration of transmembrane helical bundles ( GpA). The present method is found to perform well in each of these cases and is anticipated to be useful in the study of folding and assembly of membrane proteins as well as in structure refinement and modeling of membrane proteins where a limited number of experimental observables are available.