CompBio: Predicting Protein Folding Pathways and Protein Misfolding

蛋白质错误折叠已被证实是导致多种疾病如Creutzfeldt-Jacob病、囊性纤维化、遗传性肺气肿和某些癌症的原因，因此蛋白质折叠途径的预测是一个非常重要的问题。此外，蛋白质折叠途径的知识可以提供重要的洞察蛋白质的结构。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。我们在本提案中概述的新方法是从最终状态的折叠蛋白质开始，并学习如何以近似有序的步骤序列将蛋白质展开到其未折叠状态。利用已知的结构和一种快速的基于图的算法，沿着其能量最不稳定的接触递归地分裂结构，我们能够开发一个拓扑解折叠的通用模型。我们建议探索已知引起蛋白质折叠的突变对折叠途径的影响。（或抑制）错误折叠疾病，特别是与淀粉样纤维形成相关的疾病。我们将计算折叠中间体的分布，然后比较这些分布为已知的自然突变，导致淀粉样蛋白在细胞中的积累。更广泛的影响这一建议建立在一个成功的PI，无论是在合作研究和教育工作的良好记录。例如，Bystroff和Zaki的团队每年在RPI（1999-2004）教授NSF肖托夸夸生物信息学和生物技术新方向暑期课程。PI在为代表性不足的群体提供建议和促进研究活动方面有着良好的记录。例如，两个PI共同监督一个印第安人M.S.学生，扎基已经监督了7名女硕士。学生目前，他正在指导2名女博士生。Bystroff目前有三名非裔美国大学生研究人员，这项工作将作为一个网络服务器和开源软件提供，它可以预测展开的途径。两名全日制研究生将接受该补助金的培训。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。这一提议将支持一个持续的跨学科研究小组，该小组已促成了几个联合课程和出版物。本提案中所述的许多初步工作都是这种合作的成果。最后，这笔拨款将支持美国最强大的生物信息学教学计划之一。

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.