Tsai C J, Nussinov R
Laboratory of Mathematical Biology, NCI-FCRDC, Frederick, Maryland 21702, USA.
Protein Sci. 1997 Jan;6(1):24-42. doi: 10.1002/pro.5560060104.
We have designed an automated procedure to cut a protein into compact hydrophobic folding units. The hydrophobic units are large enough to contain tertiary non-local interactions, reflecting potential nucleation sites during protein folding. The quality of a hydrophobic folding unit is evaluated by four criteria. The first two correspond to visual characterization of a structural domain, namely, compactness and extent of isolation. We use the definition of Zehfus and Rose (Zehfus MH, Rose GD, 1986, Biochemistry 25:35-340) to calculate the compactness of a cut protein unit. The isolation of a unit is based on the solvent accessible surface area (ASA) originally buried in the interior and exposed to the solvent after cutting. The third quantity is the hydrophobicity, equivalent to the fraction of the buried non-polar ASA with respect to the total non-polar ASA. The last criterion in the evaluation of a folding unit is the number of segments it includes. To conform with the rationale of obtaining hydrophobic units, which may relate to early folding events, the hydrophobic interactions are implicitly and explicitly applied in their generation and assessment. We follow Holm and Sander (Holm L, Sander C, 1994, Proteins 19:256-268) to reduce the multiple cutting-point problem to a one-dimensional search for all reasonable trial cuts. However, as here we focus on the hydrophobic cores, the contact matrix used to obtain the first non-trivial eigenvector contains only hydrophobic contracts, rather than all, hydrophobic and hydrophilic, interactions. This dataset of hydrophobic folding units, derived from structurally dissimilar single chain monomers, is particularly useful for investigations of the mechanism of protein folding. For cases where there are kinetic data, the one or more hydrophobic folding units generated for a protein correlate with the two or with the three-state folding process observed. We carry out extensive amino acid sequence order independent structural comparisons to generate a structurally non-redundant set of hydrophobic folding units for fold recognition and for statistical purposes.
我们设计了一种自动化程序，用于将蛋白质切割成紧密的疏水折叠单元。这些疏水单元足够大，能够包含三级非局部相互作用，反映了蛋白质折叠过程中的潜在成核位点。疏水折叠单元的质量通过四个标准进行评估。前两个标准对应于结构域的视觉特征，即紧凑性和隔离程度。我们采用Zehfus和Rose（Zehfus MH，Rose GD，1986，《生物化学》25：35 - 340）的定义来计算切割后蛋白质单元的紧凑性。单元的隔离基于最初埋藏在内部且切割后暴露于溶剂的溶剂可及表面积（ASA）。第三个量是疏水性，相当于埋藏的非极性ASA相对于总非极性ASA的比例。评估折叠单元的最后一个标准是它包含的片段数量。为了符合获得可能与早期折叠事件相关的疏水单元的原理，在其生成和评估过程中隐式和显式地应用了疏水相互作用。我们遵循Holm和Sander（Holm L，Sander C，1994，《蛋白质》19：256 - 268）的方法，将多个切割点问题简化为对所有合理试验切割的一维搜索。然而，由于这里我们关注的是疏水核心，用于获得第一个非平凡特征向量的接触矩阵仅包含疏水接触，而非所有疏水和亲水相互作用。这个源自结构不同的单链单体的疏水折叠单元数据集，对于研究蛋白质折叠机制特别有用。对于有动力学数据的情况，为一种蛋白质生成的一个或多个疏水折叠单元与观察到的二态或三态折叠过程相关。我们进行广泛的与氨基酸序列顺序无关的结构比较，以生成用于折叠识别和统计目的的结构非冗余疏水折叠单元集。
