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、遗传性肺气肿和某些癌症。此外，蛋白质折叠途径的知识可以为蛋白质结构提供重要的见解。为了使基于途径的结构预测方法成为现实，需要对合理的蛋白质折叠途径进行建模和验证。我们在这项提议中概述的新方法是从处于最终状态的折叠蛋白质开始，并学习如何以近似有序的步骤序列展开蛋白质，以达到其展开状态。这种序列的反转代表了一种合理的蛋白质折叠途径。利用已知的结构和一种快速的、基于图的算法，在其能量最不稳定的接触上进行结构的递归分裂，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，特别是那些与淀粉样蛋白纤维形成相关的突变。我们将计算折叠中间体的分布，然后将这些分布与已知导致淀粉样蛋白在细胞中积聚的自然突变进行比较。更广泛的影响该提案建立在pi在合作研究和教育工作方面的成功记录的基础上。例如，Bystroff和Zaki在1999年至2004年期间经常在RPI教授sf肖托夸生物信息学和生物技术新方向暑期课程。私人顾问在为代表性不足的群体提供咨询和促进研究活动方面有着良好的记录。例如，两位pi共同监督了一个美洲原住民的m.s.。扎基曾指导过7名女护士。学生。目前指导2名女博士生。Bystroff目前有三名非裔本科研究员。这项提议的工作将作为网络服务器和开源软件向公众开放，以预测未来的发展路径。两名全日制研究生将在此资助下接受培训。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。这项建议将支持一个持续的跨学科研究小组，该小组已联合举办了几门课程和出版物。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，这笔拨款将支持全国最强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.