SELF RECOGNITION IN GLOBULAR PROTEINS

蛋白质折叠问题的解决对 对自然产生的蛋白质及其故意的理解 工程设计的对应物。我们的主要目标是阐明 管理蛋白质折叠的立体化学代码，并用它来表达 一个实用的折叠算法。 特别令人感兴趣的是阿尔法螺旋，首先由Pauling和 同事。螺旋是蛋白质结构的标志，也是许多努力的标志 旨在了解哪些序列可以形成稳定的序列 螺旋。我们实验室的两条交汇点都集中在 分别在螺旋内的中心残基和末端残基上。为 中心残基，假设侧链熵是 控制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氢键“封顶” 和其他不满意的最初的四个酰胺氢或最终的四个 主链上的羰基氧是螺旋结构中的主要因素 专一性。这项工作的结果可以被预测性地使用， 与经验策略不同，这样的预测是基于似是而非的。 热力学。 这项工作正在顺利进行，将扩大到包括其他 二级结构的分类也是如此。遵循所使用的方法 对于螺旋，β-折叠中的残基可以在每个 微环境，在中间或边缘或中心或 绞股线的末端。也可以包括非重复结构。 初步结果表明，许多残留物明显地 可以理解的，明确定义的二级结构偏好。为 例如，处于展开状态的Valine可以填充所有三条侧链 构象几乎相等，但基本上只有一个构象，当 呈螺旋状。相应的能量损失(T-增量-S)仅由 边链熵的约化约为RTln3量级 生理KT。这些能量项，使残基偏向于 与其他类型的次要结构相比，尽管个别结构不大，但有以下几种 当加到整个螺旋或薄片上时，在总体上意义重大。 给定一类二级结构对侧链的影响 残基的熵和/或分子内氢键是 相当于一种立体化学密码。

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.