Toward the understanding of MNEI sweetness from hydration map surfaces
Toward the understanding of MNEI sweetness from hydration map surfaces
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DOI：
10.1529/biophysj.105.073171
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发表时间：
2006-05-01
影响因子：
3.4
通讯作者：
Fraternali, F
中科院分区：
文献类型：
--
作者：
De Simone, A;Spadaccini, R;Fraternali, F
甜蛋白与其受体(一种G蛋白偶联受体)的结合机制不受直接结构信息的支持。原则上，负责生物活性的关键基团(葡萄糖基)可以定位在一个小的结构单元(甜指)上，也可以分布在更大的表面积上。最近提出的一个模型，称为“楔形模型”，暗示了与受体相互作用的大表面。为了更详细地探索这一模型，有必要检查甜蛋白表面的物理化学特征，因为相对于小甜味剂，它们与受体的相互作用更依赖于界面的一般物理化学性质，如静电势和水合作用。在本研究中，我们在显式水中对甜蛋白MNEI及其结构突变体G-16A进行了详尽的分子动力学模拟，G-16A的甜度比MNEI低一个数量级。从分子动力学模拟计算的溶剂密度和自扩散表明，一个可能的相互作用区域由四个四面体排列而成，其形状与受体表面的空穴形状互补，与楔形模型一致。建议的相互作用区域与已知的突变数据惊人地一致。此外，这两种蛋白质中唯一的螺旋的不对称水化暗示了这种二级结构元素在结合过程中定位蛋白质的特定作用。
The binding mechanism of sweet proteins to their receptor, a G-protein-coupled receptor, is not supported by direct structural information. In principle, the key groups responsible for biological activity (glucophores) can be localized on a small structural unit (sweet finger) or spread on a larger surface area. A recently proposed model, called "wedge model", implies a large surface of interaction with the receptor. To explore this model in greater detail, it is necessary to examine the physicochemical features of the surfaces of sweet proteins, since their interaction with the receptor, with respect to that of small sweeteners, is more dependent on general physicochemical properties of the interface, such as electrostatic potential and hydration. In this study, we performed exhaustive molecular dynamics simulations in explicit water of the sweet protein MNEI and of its structural mutant G-16A, whose sweetness is one order of magnitude lower than that of MNEI. Solvent density and self-diffusion calculated from molecular dynamics simulations suggest a likely area of interaction delimited by four stretches arranged as a tetrahedron whose shape is complementary to that of a cavity on the surface of the receptor, in agreement with the wedge model. The suggested area of interaction is amazingly consistent with known mutagenesis data. In addition, the asymmetric hydration of the only helix in both proteins hints at a specific role for this secondary structure element in orienting the protein during the binding process.