SELF-RECOGNITION IN GLOBULAR PROTEINS

蛋白质折叠问题的解决方案对于一个 了解天然存在的蛋白质及其故意 工程对应物。 我们的主要目标是阐明 控制蛋白质折叠的立体化学密码， 一种实用的折叠算法。 特别令人感兴趣的是α-螺旋，首先由Pauling提出， 同事 螺旋是蛋白质结构的标志， 已经被导向理解哪些序列可以形成稳定的 螺旋 我们实验室的两条研究路线都集中在 分别在螺旋内的中心和末端残基上。 为 中心残基，假设侧链熵是 决定螺旋倾向的主要因素。 对于末端残基， 假设侧链极性基团之间的“封端”氢键 以及其它不饱和的起始四个酰胺氢或最后四个酰胺氢 主链上的羰基氧是形成螺旋的主要因素 的特异性 这项工作的结果可以预测性地使用，并且， 与经验策略不同，这种预测是建立在似是而非的 热力学 这项工作正在顺利进行，将扩大到包括其他 二级结构也是如此。 按照所采用的方法， 对于螺旋，β-折叠中的残基可以在每个 微环境，无论是在中间或边缘股和在中心或 链的末端。 也可以包括非重复结构。 初步结果表明，许多残留物显然 明确的二级结构偏好。 为 例如，处于未折叠状态的缬氨酸可以填充所有三个侧链， 构象几乎相等，但基本上只有一个构象时， 呈螺旋状。 相应的能量损失（T-delta-S）仅由于 侧链熵的减少约为RTln 3，数量级为 生理kT 这些能量项，使剩余偏向于 二级结构的类型，虽然个别温和，是 当在整个螺旋或片上求和时，在聚合中是显著的。 一类二级结构对侧链的影响 残基的熵和/或分子内氢键是 相当于一个立体化学密码。

The solution to the protein folding problem is critical to an understanding of the naturally occurring proteins and their deliberately engineered counterparts. Our principal goal is to elucidate the stereochemical code that governs protein folding and use it to formulate a practical folding algorithm. Of particular interest is the alpha-helix, first proposed by Pauling and coworkers. Helices are a hallmark of protein structure, and much effort has been directed towards understanding which sequences can form stable helices. Two converging lines of investigation in our lab have focused separately on the central and terminal residues within the helix. For central residues, it is hypothesized that sidechain entropy is the principal factor that governs helix propensity. For terminal residues, it is hypothesized that "capping" H-bonds between sidechain polar groups and the otherwise unsatisfied initial four amide hydrogens or final four carbonyl oxygens in the mainchain are the major factor in helix specificity. Results from this work can be used predictively, and, unlike empirical strategies, such predictions are grounded in plausible thermodynamics. This work, which is well underway, will be extended to include other categories of secondary structure as well. Following the approach used for helices, residues in beta-sheet can be modelled in each microenvironment, in either middle or edge strands and at the center or terminus of the strand. Nonrepetitive structure can also be included. Preliminary results suggest that many residues have clearly understandable, sharply defined secondary structure preferences. For example, valine in the unfolded state can populate all three sidechain conformers almost equivalently, but essentially only one conformer when in a helix. The corresponding energy loss (T-delta-S) due solely to the reduction in sidechain entropy is approximately RTln3, of order physiological kT. These energy terms, which cause residues to favor one type of secondary structure over others, though individually modest, are significant in the aggregate, when summed over an entire helix or sheet. The effect of a given class of secondary structure on the sidechain entropy and/or intra-molecular hydrogen bonding of a residue is tantamount to a stereochemical code.