UKRI/BBSRC - NSF/BIO: Modeling of protein interactions to predict phenotypic effects of genetic mutations

蛋白质复合体的结构对于解释基因突变是必不可少的。在基于知识的方法的进步和对蛋白质结构和功能的物理原理的更好理解的推动下，蛋白质及其相互作用的结构建模方法正在迅速发展。从高通量测序中可以获得关于人类遗传变异的大量信息，包括大量单一氨基酸的变化。该项目的重点是将建模技术应用于公共资源的开发，将结构建模与遗传氨基酸变体相结合，并评估其功能影响。这项研究的长期目标是深入了解生命系统中分子过程的基本原理，以及基因突变对细胞机制的影响。这个合作项目结合了美国蛋白质相互作用建模团队和英国蛋白质结构预测和错义变异效应团队高度互补的专业领域。这些团队将继续协调基于该项目的研究和培训活动，与当地、国内和国际的研究生和本科生项目合作。少数民族学生和女性将参与这项研究的不同部分。该项目将加强研究和教育的基础设施。美国和英国的团队在开发和传播公共资源方面有着广泛的记录，世界各地的许多研究人员都在使用这些资源。项目参与者将在各种多学科会议和研讨会上积极展示他们的成果。将预测的复合体与遗传变异结合在一起的方法及其表型效应评估将进一步发展。该项目的目标是：(1)蛋白质相互作用组的结构模型；(2)遗传变异的表型效应的评估；(3)蛋白质相互作用组的结构表征和遗传突变的表型效应的公共资源。蛋白质复合体结构特征的计算方法将结合深度学习在蛋白质结构和组装预测中的应用的最新进展。预测突变效应的立体化学方法将包括为变异侧链建立可接受的构象模型，并评估相互作用的变化。GWYRE资源将纳入模式生物的蛋白质复合体，由错义变体的表型效应注释。项目成果将通过开发蛋白质相互作用的结构特征和基因突变的表型效应评估的综合公共资源，对研究领域产生重大影响。该项目的结果将在http://www.gwyre.org和http://vakser.compbio.ku.edu上公布，http://www.sbg.bio.ic.ac.uk.This奖反映了国家科学基金会的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Structures of protein complexes are essential for interpretation of genetic mutations. Approaches to structural modeling of proteins and their interactions are rapidly developing, powered by advances in knowledge-based methods and better understanding of physical principles of protein structure and function. A vast amount of information on human genetic variation, including numerous single amino acid changes, is available from high-throughput sequencing. The project focuses on application of modeling techniques to the development of a public resource incorporating structural modeling with genetic amino acid variants and assessment of their functional impact. The long-term goals of this research are to gain insights into fundamental principles of molecular processes in living systems and the effect of genetic mutations on cellular mechanisms. This collaborative project combines highly complementary areas of expertise of the US team on modeling of protein interactions, and the UK team on protein structure prediction and missense variant effects. The teams will continue coordinating research and training activities, based on the project, with graduate and undergraduate programs locally, nationally and internationally. Minority students and women will be involved in different parts of the research. The project will enhance infrastructure for research and education. The US and UK teams have an extensive record of developing and disseminating public resources, used by many researchers worldwide. The project participants will be actively presenting their results at various multidisciplinary conferences and workshops.The approach incorporating predicted complexes in model organisms with genetic variants and their phenotypic effect assessment will be further developed. The objectives of the project are: (1) structural modeling of protein interactome; (2) assessment of phenotypic effects of genetic variation; and (3) public resource for structural characterization of protein interactome and phenotypic effects of genetic mutations. Computational approaches to structural characterization of protein complexes will incorporate recent advances in application of Deep Learning to prediction of protein structures and assemblies. The stereochemical approach to prediction of the mutation effect will involve modeling acceptable conformations for the variant side chains and evaluating the change in interactions. The GWYRE resource will incorporate protein complexes for model organisms, annotated by the phenotypic effects of missense variants. The project outcome will have a significant impact on the research field by development of the integrated public resource for structural characterization of protein interactomes and assessment of the phenotypic effects of genetic mutations. The results of the project will be available at http://www.gwyre.org and also at http://vakser.compbio.ku.edu and http://www.sbg.bio.ic.ac.uk.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.