Empirical Potential Functions for Prediction of Protein Folding

生物物理学中的一个重大挑战是根据氨基酸序列预测蛋白质折叠。研究者和同事们已经确定了一个经验数学函数，可以识别许多蛋白质的天然构象，而不是成千上万的由其他蛋白质晶体结构组成的诱饵构象。他们现在正在通过测试不同的功能形式、针对更多的原生折叠进行训练以及使用更广泛的非原生折叠类对其进行挑战来改进此功能。如果该函数足够平滑，它可以作为结构预测算法的一部分引导搜索到本地结构。在当前对人类基因组计划的兴奋中，很容易忘记基因序列就像房子的蓝图，而我们更关心的是房子而不是蓝图。目前，我们还不知道大约三分之一的序列一旦被翻译成蛋白质——使细胞工作的三维分子机器——所起的生物学和医学作用。蛋白质的功能主要取决于这些长链如何折叠成特定的形状。这个项目是通过试图预测它们的三维结构来理解这数千个神秘序列。这个实验室的工作人员已经开发出一种计算机方法，可以从一排错误的序列中选择正确的结构，就像在一次大型的选择题考试中一样。他们现在正朝着回答作文考试的方向发展，在作文考试中，顺序是给定的，结构不仅要识别，而且要构建。在做到这一点之前，大规模测序项目的大部分价值都无法实现。

One of the grand challenges in biophysics is the prediction of protein folding from the amino acid sequence. The investigator and coworkers have determined an empirical mathematical function that can recognize the native conformation for many proteins compared to many thousands of decoy conformation constructed from pieces of other protein crystal structures. They are now improving this function by testing different functional forms, training against more natives, and challenging it with wider classes of nonnative folds. If the function can be made smooth enough, it could quide a search toward the native structure as part of a structure prediction algorithm. In the current excitement over the human genome project, it is easy to forget that gene sequences are like blueprints for a house, and we are more concerned with the house than the blueprints. At the moment, we have no idea about the biological and medical role that about a third of the sequences play once they are translated into proteins, the three-dimensional molecular machines that make cells work. How proteins function depends critically on how these long chains fold up into particular shapes. This project is concerned with making sense of those thousands of mysterious sequences by trying to predict their three-dimensional structures. Workers in this laboratory have developed computer methods to choose the correct structure for a given sequence out of a lineup of many incorrect ones, as in a huge multiple choice exam. They are now moving toward answering an essay exam, where the sequence is given, and the structure must not merely be recognized, but constructed. Until this can be done, much of the value of the massive sequencing projects cannot be realized.