Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, USA.
Protein Sci. 2010 Jan;19(1):141-54. doi: 10.1002/pro.288.
We explore the question of whether local effects (originating from the amino acids intrinsic secondary structure propensities) or nonlocal effects (reflecting the sequence of amino acids as a whole) play a larger role in determining the fold of globular proteins. Earlier circular dichroism studies have shown that the pattern of polar, non polar amino acids (nonlocal effect) dominates over the amino acid intrinsic propensity (local effect) in determining the secondary structure of oligomeric peptides. In this article, we present a coarse grained computational model that allows us to quantitatively estimate the role of local and nonlocal factors in determining both the secondary and tertiary structure of small, globular proteins. The amino acid intrinsic secondary structure propensity is modeled by a dihedral potential term. This dihedral potential is parametrized to match with experimental measurements of secondary structure propensity. Similarly, the magnitude of the attraction between hydrophobic residues is parametrized to match the experimental transfer free energies of hydrophobic amino acids. Under these parametrization conditions, we systematically explore the degree of frustration a given polar, non polar pattern can tolerate when the secondary structure intrinsic propensities are in opposition to it. When the parameters are in the biophysically relevant range, we observe that the fold of small, globular proteins is determined by the pattern of polar, non polar amino acids regardless of their instrinsic secondary structure propensities. Our simulations shed new light on previous observations that tertiary interactions are more influential in determining protein structure than secondary structure propensity. The fact that this can be inferred using a simple polymer model that lacks most of the biochemical details points to the fundamental importance of binary patterning in governing folding.
我们探讨了局部效应（源于氨基酸固有二级结构倾向）或非局部效应（反映氨基酸整体序列）在确定球状蛋白质折叠中哪个起更大的作用。早期的圆二色性研究表明，极性、非极性氨基酸模式（非局部效应）在确定寡肽的二级结构时，比氨基酸固有倾向（局部效应）更占主导地位。在本文中，我们提出了一个粗粒度的计算模型，使我们能够定量估计局部和非局部因素在确定小的球状蛋白质的二级和三级结构中的作用。通过二面角势项来模拟氨基酸固有二级结构倾向。该二面角势项被参数化以匹配二级结构倾向的实验测量。类似地，疏水残基之间的吸引力的大小被参数化以匹配疏水氨基酸的实验转移自由能。在这些参数化条件下，我们系统地探索了在二级结构固有倾向与之相反时，给定的极性、非极性模式可以容忍的受挫程度。当参数处于生物物理相关范围内时，我们观察到，无论其固有二级结构倾向如何，小的球状蛋白质的折叠都由极性、非极性氨基酸的模式决定。我们的模拟结果为先前的观察结果提供了新的见解，即三级相互作用在确定蛋白质结构方面比二级结构倾向更有影响力。这可以通过缺乏大多数生化细节的简单聚合物模型推断出来，这表明二进制模式在控制折叠方面具有基本的重要性。
