EAGER: III: Collaborative Research: RUI: In silico Algorithm for Assessing the Effects of Amino Acid Insertion and Deletion Mutations

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This project proposes to advance current capabilities in predicting the impact of changes to protein sequence to changes in three-dimensional structure and function. The investigators focus on amino-acid insertions and deletions. This expansion is warranted, as changes to DNA include not just mutations but also insertions and deletions of entire fragments. A timely example of the need for the capabilities that will be developed in this project is the fast evolution observed in near real-time in SARS-Cov2. Many of the changes are concentrated in the sequence of the spike protein that binds to the lung receptors. Recent reports indicate that such changes are affecting changes to the structure of this protein and possibly its function. The problem of predicting the impact of changes to sequence to the structure and function of a protein is a hallmark problem in molecular biology. In this project, the investigators combine sequence data, a promising geometric treatment to predict changes to structure, and informatics techniques for predicting changes to function. The activities in this project constitute promising exploratory research.This project makes two key contributions. First, an inverse kinematics approach predicts sub-sequence configurations impacted by the insertion or deletion of amino acids and then accommodates such configurations via a constrained optimization approach in a physically-realistic tertiary structure of the entire protein sequence. Second, graph-rigidity analysis is employed to analyze computed structures and predict rigidity data. Coupled with evolutionary conservation, the data are employed to train machine learning models capable of predicting the stability of sequences of interest. The investigators have a track record of collaborative dissemination. The developed algorithms will be made freely available to the scientific community. In addition, the investigators have made increasing student diversity one of their top priorities. The investigators will continue to expand their efforts in successful mentoring of undergraduate students, including undergraduates from other STEM majors. In close coordination, the investigators will actively work with women and students from under-represented groups through several programs. One of them builds off an existing NSF award. The investigators will also leverage outreach efforts such as the Bridges to the Baccalaureate program, the University of Massachusetts Boston Women in Science club, and the Initiative for Maximizing Student Development.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.