CompBio: Predicting Protein Folding Pathways and Protein Misfolding

CompBio：预测蛋白质折叠途径和蛋白质错误折叠

• 批准号: 0432098
• 负责人: Mohammed Zaki
• 金额: $ 20万
• 依托单位: Rensselaer Polytechnic Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0432098&HistoricalAwards=false
• 关键词: CompBio; Predicting; Protein; Folding; Pathways

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.

蛋白质折叠途径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克雅氏病、囊性纤维化、遗传性肺气肿和某些癌症等多种疾病的病因。此外，对蛋白质折叠途径的了解可以使人们对蛋白质的结构有重要的了解。为了使基于路径的结构预测方法成为现实，需要对合理的蛋白质折叠路径进行建模和验证。本提案中概述的新方法是从最终状态的折叠蛋白质开始，并学习如何以大致有序的步骤序列将蛋白质展开到其未折叠状态。这样一个序列的反转代表了一个合理的蛋白质折叠途径。使用已知的结构和基于图形的快速算法，沿着其最不稳定的接触点递归分裂结构，我们能够开发一个拓扑展开的通用模型。我们建议探索已知会导致（或抑制）错误折叠疾病的突变对折叠途径的影响，特别是与错误折叠疾病相关的突变 淀粉样纤维的形成。我们将计算折叠中间体的分布，然后将这些分布与已知会导致细胞中淀粉样蛋白积累的自然突变进行比较。 更广泛的影响 该提案建立在 PI 的成功记录之上，包括合作研究和教育工作。例如，Bystroff 和 Zaki 团队在 RPI 每年举办一次关于生物信息学和生物技术新方向的 NSF Chautauqua 夏季课程（1999-2004 年）。 PI 拥有为代表性不足的群体提供建议和促进研究活动的记录。例如，两位 PI 共同监督了一位美洲原住民硕士。学生，Zaki 指导过 7 名女性硕士。学生。目前他正在指导两名女博士生。 Bystroff 目前拥有三名非裔美国本科研究人员。拟议的工作将作为网络服务器和开源软件公开发布，以预测展开的路径。两名全日制研究生将接受这笔资助的培训。本科生，包括代表性不足的群体，将继续在我们的研究工作中发挥重要作用。该提案将支持一个持续的跨学科研究团队，该研究团队已经推出了一些联合课程和出版物。本提案中描述的大部分前期工作都是此次合作的成果。最后，这笔赠款将支持美国最强大的生物信息学教学项目之一。