加州康奈爾大學(xué)的研究者和他們斯克利普斯研究院（Scripps Research Institute）的同事一起找到支持一種沿用已久的關(guān)于蛋白怎樣折疊形成獨(dú)特的形狀和生物功能的理論的實(shí)驗(yàn)證據(jù)。這一研究成果公布在美國國家科學(xué)院院刊PNAS上,。
該理論提出蛋白沿著包含有非極性基團(tuán)或者含有不帶電荷的分子的氨基酸鏈處開始折疊,，并通過這些非極性基團(tuán)的組合進(jìn)一步折疊。利用分開水和油的相同的原理,，這些分子具有疏水性——它們排斥水分子并相互聚集起來,。
在細(xì)胞內(nèi)基于水的流動性作用下，核糖體制造并釋放出長肽鏈,，這些肽鏈迅速折疊成具有生物功能的結(jié)構(gòu),。該理論提出沿著肽鏈具有很多疏水集團(tuán)依賴自身折疊的位點(diǎn)，生成了小型的非極性疏水袋（hydrophobic pocket）”,。
“是什么趨勢這些多肽鏈折疊呢,？”康奈爾大學(xué)化學(xué)與生物化學(xué)名譽(yù)教授Harold Scheraga問道。“這曾經(jīng)是我以前一段時間的研究主題,，引用該理論的實(shí)驗(yàn)證據(jù)將為進(jìn)一步弄清楚折疊途徑的步驟的計(jì)算工作提供了合理的基礎(chǔ),。”
“蛋白折疊是蛋白化學(xué)領(lǐng)域的前沿難題”
Scheraga說，他指出預(yù)測一種蛋白折疊的地方將為理解這種蛋白錯誤折疊所帶來的疾病如：阿滋海默癥和囊性纖維癥等提供幫助,，并且可以幫助設(shè)計(jì)作用與蛋白的新藥,，甚至創(chuàng)造一種具有新功能的蛋白。
該理論是基于兩種方法的基礎(chǔ)上提出的,，指出蛋白最初的折疊位點(diǎn)出現(xiàn)在多肽鏈的非極性基團(tuán)處,。該項(xiàng)目的首要作者，來自Scripps研究院的兩位分子生物學(xué)教授H. Jane Dyson 和Peter Wright利用一種實(shí)驗(yàn)核磁共振的方法來確證了該理論的兩種方法預(yù)測的結(jié)果,。
第一種方法利用超級計(jì)算機(jī)計(jì)算出過肽鏈轉(zhuǎn)換成疏水袋所需的能量,，這些折疊在需要最少能量的地方發(fā)生。通過找出非極性基團(tuán)出現(xiàn)的位置,，研究者們能更好的理解折疊沿著線形肽鏈發(fā)生的位置,。
第二種方法通過追蹤蛋白形成天然結(jié)構(gòu)所需的步驟來繪制出折疊完成的蛋白,。這種方法描繪了蛋白折疊的三個階段。首先描繪出鄰近氨基酸之間的短程接觸,，揭示了最初的非極性折疊,。接下來的兩個階段表明在沿著肽鏈較遠(yuǎn)的點(diǎn)之間的地方發(fā)生折疊。第二次折疊會形成兩個或者三個疏水袋,。
這兩種方法合起來運(yùn)用到研究中,，可以查明肽鏈上非極性片斷的位置、最初折疊發(fā)生的地方,，和最終折疊形成的形式,。
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.
