CompBio: Predicting Protein Folding Pathways and Protein Misfolding

蛋白质折叠途径的预测是一个非常重要的问题，因为蛋白质错误折叠已被确定为多种疾病的原因，如克雅氏病、囊性纤维化、遗传性肺气肿和一些癌症。此外，对蛋白质折叠途径的了解可以对蛋白质的结构提供重要的洞察。为了使基于途径的结构预测方法成为现实，需要对看似合理的蛋白质折叠途径进行建模和验证。我们在本提案中概述的新方法是从折叠蛋白质的最终状态开始，并学习如何以大致有序的步骤将蛋白质展开到其展开状态。利用已知的结构和基于图的快速递归分裂算法，我们能够开发出一个拓扑展开的通用模型。我们建议探索已知的导致(或抑制)错误折叠疾病的突变对折叠路径的影响，特别是与淀粉样纤维形成相关的突变。我们将计算折叠中间体的分布，然后比较这些分布与已知导致细胞内淀粉样蛋白积累的自然突变的分布。广泛影响这项建议建立在PI成功的成功记录基础上，无论是合作研究还是教育努力。例如，Bystroff和Zaki在RPI有团队taughtNSF Chautauqua夏季生物信息学和生物技术新方向课程(1999-2004)。私人投资机构有在代表不足的群体中为研究活动提供建议和促进研究活动的记录。例如，两个PI共同指导了一名美洲原住民硕士学生，而扎基则指导了7名女性硕士学生。目前，他正在指导两名女性博士生。Bystroff目前有三名非裔美国本科生研究人员。这项拟议的工作将以网络服务器和开源软件的形式公开提供，该软件可以预测未来的发展道路。两名全日制研究生将接受这笔助学金的培训。本科生，包括代表不足的群体，将继续在我们的研究努力中发挥重要作用。这项提议将支持一个持续的跨学科研究小组，该小组已经产生了几个联合课程和出版物。本提案中描述的大部分初步工作都是这种合作的成果。最后，这笔资金将支持美国最强大的生物信息学教学项目之一。

Intellectual Merit Protein folding pathway prediction is a very important problem since proteinmisfolding has been identified as the cause of several diseases such as Creutzfeldt-Jacob disease,cystic fibrosis, hereditary emphysema and some cancers. Furthermore, knowledge of pathways forprotein folding can give important insight into the structure of proteins. To make pathway basedapproaches to structure prediction a reality, plausible protein folding pathways need to be modeledand validated.Our novel approach outlined in this proposal is to start with a folded protein in its final stateand learn how to unfold the protein in an approximately ordered sequence of steps, to its unfoldedstate. The reversal of such a sequence then represents a plausible protein folding pathway.Using the known structure and a fast, graph-based algorithm for recursive splitting of the structurealong its most energetically labile contacts, we are able to develop a general model for topologicalunfolding.We propose to explore the effect on the folding pathway of mutations that are known to cause(or suppress) misfolding diseases, especially those associated with amyloid fiber formation. Wewill calculate the distribution of folding intermediates and then compare these distributions fornatural mutatations that are known to cause amyloid accumulation in the cell.Broader Impact This proposal builds on a proven track record of success of the PIs, both incollaborative research and educational efforts. For instance, Bystroff and Zaki have team taughtNSF Chautauqua Summer Course on New Directions in Bioinformatics and Biotechnology, heldanually at RPI (1999-2004). The PIs have a track record of advising and promoting researchactivity in under-represented groups. For instance, both PIs jointly supervised a Native AmericanM.S. student, and Zaki has supervised 7 femaleM.S. students. Currently he is supervising 2 femalePhD students. Bystroff currently has three African-American undergraduate researchers.The proposed work will be made publically available as a web server, and also open-sourcesoftware, that predicts the unfolding pathway. Two full-time graduate students will be trainedon this grant. Undergraduates, including underrepresented groups, will continue to play a largepart in our research efforts. This proposal will support a continuing inter-disciplinary researchteam, which has resulted in several joint courses and publications. Much of the preliminary workdescribed in this proposal is the fruit of this collaboration. Finally this grant will support one ofthe nation's strongest teaching programs in bioinformatics.