加州康奈尔大学的研究者和他们斯克利普斯研究院（Scripps Research Institute）的同事一起找到支持一种沿用已久的关于蛋白怎样折叠形成独特的形状和生物功能的理论的实验证据。这一研究成果公布在美国国家科学院院刊PNAS上。
该理论提出蛋白沿着包含有非极性基团或者含有不带电荷的分子的氨基酸链处开始折叠，并通过这些非极性基团的组合进一步折叠。利用分开水和油的相同的原理，这些分子具有疏水性——它们排斥水分子并相互聚集起来。
在细胞内基于水的流动性作用下，核糖体制造并释放出长肽链，这些肽链迅速折叠成具有生物功能的结构。该理论提出沿着肽链具有很多疏水集团依赖自身折叠的位点，生成了小型的非极性疏水袋（hydrophobic pocket）”。
“是什么趋势这些多肽链折叠呢？”康奈尔大学化学与生物化学名誉教授Harold Scheraga问道。“这曾经是我以前一段时间的研究主题，引用该理论的实验证据将为进一步弄清楚折叠途径的步骤的计算工作提供了合理的基础。”
“蛋白折叠是蛋白化学领域的前沿难题”
Scheraga说，他指出预测一种蛋白折叠的地方将为理解这种蛋白错误折叠所带来的疾病如：阿滋海默症和囊性纤维症等提供帮助，并且可以帮助设计作用与蛋白的新药，甚至创造一种具有新功能的蛋白。
该理论是基于两种方法的基础上提出的，指出蛋白最初的折叠位点出现在多肽链的非极性基团处。该项目的首要作者，来自Scripps研究院的两位分子生物学教授H. Jane Dyson 和Peter Wright利用一种实验核磁共振的方法来确证了该理论的两种方法预测的结果。
第一种方法利用超级计算机计算出过肽链转换成疏水袋所需的能量，这些折叠在需要最少能量的地方发生。通过找出非极性基团出现的位置，研究者们能更好的理解折叠沿着线形肽链发生的位置。
第二种方法通过追踪蛋白形成天然结构所需的步骤来绘制出折叠完成的蛋白。这种方法描绘了蛋白折叠的三个阶段。首先描绘出邻近氨基酸之间的短程接触，揭示了最初的非极性折叠。接下来的两个阶段表明在沿着肽链较远的点之间的地方发生折叠。第二次折叠会形成两个或者三个疏水袋。
这两种方法合起来运用到研究中，可以查明肽链上非极性片断的位置、最初折叠发生的地方，和最终折叠形成的形式。
英文原文：
How and where proteins fold into their critical shapes
Experimental evidence provided by a Cornell researcher and colleagues at the Scripps Research Institute in La Jolla, Calif., support a long-held theory of how and where proteins fold to create their characteristic shapes and biological functions.
The theory proposes that proteins start to fold in specific places along an amino acid chain (called a polypeptide chain) that contains nonpolar groups, or groups of molecules without a charge, and continue to fold by aggregation, i.e., as several individuals of these nonpolar groupings combine. Using the same principle that separates oil and water, these molecules are hydrophobic -- they avoid water and associate with each other.
In the water-based cell fluid, where long polypeptide chains are manufactured and released by ribosomes, the polypeptide chains rapidly fold up into their biologically functional structure. The theory proposes that there are sites along the polypeptide chains where hydrophobic groups initially fold in on themselves, creating small nonpolar (hydrophobic) pockets that are protected from the water.
"What drives this polypeptide chain to fold up?" asked Harold Scheraga, professor emeritus of chemistry and chemical biology at Cornell and a co-author of a paper published in the Aug. 29 issue of the Proceedings of the National Academy of Sciences (and available online). "That has been the subject of my investigations for some time, and the cited experimental verification of the theory provides a sound basis for further computational work to identify the specific steps in the folding pathway.
"Protein folding is a frontier problem in protein chemistry," said Scheraga, noting that an ability to predict how and where proteins fold could lead to understanding such protein misfolding diseases as Alzheimer's and cystic fibrosis, designing drugs that act on proteins and even creating designer proteins with new functions.
The theory is based on two methods to show that initial folding sites occur among nonpolar groups in a polypeptide chain. Lead author H. Jane Dyson and Peter Wright, both professors of molecular biology at the Scripps Research Institute, used an experimental nuclear magnetic resonance procedure to validate the predicted results of the two theoretical methods.
The first method used supercomputers to calculate the energy required to convert a polypeptide chain into a collapsed hydrophobic pocket. The folds occur in several places that require the least possible energy to maintain. By finding these places where the nonpolar groups exist, the researchers better understand where folding occurs along a linear polypeptide chain.
The second method involved mapping a folded protein by tracing the folding steps required to arrive at the protein's native structure. This method mapped three stages of folding. First, the short-range contacts between amino acids that are very close to each other were mapped, revealing the initial nonpolar (hydrophobic) folds. The next two stages show folds that occur between points that are farther from each other along the polypeptide chain. These secondary folds may attach two or three hydrophobic pockets.
These two methods were used together in this study to pinpoint where on a polypeptide chain the nonpolar segments occur and where initial folding takes place and then propagates to the final folded form.
