Folding Determinants of beta-Hairpin Peptides

描述（申请人提供）：随着基因组学的快速发展，下一个主要任务是确定新发现基因编码的蛋白质的结构和功能。然而，目前对蛋白质结构的预测能力是有限的，部分原因是定义单个低能折叠的因素尚未得到很好的理解。蛋白质从头设计已经证明，疏水和亲水残基的简单二进制编码是过于简单的模型来定义天然样结构。为了深入了解有助于蛋白质折叠特异性的因素，我们正在研究极化C-H基团与芳环的相互作用通过弱极性“疏水”相互作用提供蛋白质结构特异性的能力。在蛋白质中，这种类型的相互作用包括例如两个芳香族侧链之间的边-面相互作用、赖氨酸侧链与芳香族基团的相互作用以及碳水化合物的轴向氢与碳水化合物结合蛋白中芳香环的x-云的相互作用。我们希望这些C...（相互作用将为蛋白质结构提供稳定性和特异性，因为除了疏水性和货车范德华组分之外，相互作用由贫电子C-H和芳环的x-云之间的静电相互作用组成。我们将研究模型B-发夹肽中这些相互作用的性质，并确定它们对B-发夹中链寄存器特异性的影响。随后，我们将确定它们对蛋白质泛素折叠的影响，泛素已被证明通过B-发夹的成核折叠。

DESCRIPTION (provided by applicant): With rapid advances in genomics, the next major undertaking is to determine the structure and function of the proteins encoded by newly discovered genes. However, current predictive ability for protein structure is limited, in part because the factors that define a single low energy fold are not yet well understood. Protein de novo design has demonstrated that simple binary coding of hydrophobic and hydrophilic residues is too simplistic a model to define a native-like structure. To gain insight into the factors that contribute to specificity in protein folding, we are investigating the ability of interactions of polarized C-H groups with aromatic rings to provide specificity to protein structure through weakly polar "hydrophobic" interactions. In proteins, this type of interaction includes, for example, edge-face interactions between two aromatic sidechains, the interaction of a lysine sidechain with an aromatic group, and the interaction of the axial hydrogens of carbohydrates with the x-cloud of an aromatic ring in carbohydrate binding proteins. We expect that these C-H...( interactions would provide stability and specificity to protein structure because the interaction consists of an electrostatic interaction between the electron-poor C-H and the x-cloud of the aromatic ring, in addition to hydrophobic and van der Waals components. We will investigate the nature of these interactions in model B-hairpin peptides and determine their impact on specificity of strand register in B-hairpins. Subsequently, we will determine their effect on folding of the protein ubiquitin, which has been shown to fold via the nucleation of a B-hairpin.