PROJECT SUMMARY
Research Strategy
Two of the biggest challenges in molecular biomedical research are (1) the lack of technologies for detailed
investigation of protein conformations in the cell or the native environment, and (2) a dearth of data on protein
conformational dynamics for large proteins and across time scales. This proposal addresses both these grand
challenges head-on by developing two closely related technologies: high-throughput disulfide scanning, which
will bridge the gap between in vitro and in vivo structural biology by revealing protein structures in both contexts,
and single-molecule FRET scanning, which will reveal both average conformation and pairwise distance
fluctuations across thousands of residue pairs within a protein in a massively parallel format. I will not only
develop these powerful techniques, but also apply them to key biomedical questions: the role of conformational
plasticity in the function of chaperones; the role of conformational dynamics in antibiotic susceptibility of bacterial
transpeptidases; phenotypic effects of kinetically trapped and non-native protein conformations; and structural
basis of genotype-phenotype relationships.
Candidate and Environment
I am a highly trained experimental protein biochemist and biophysicist with extensive experience investigating
the roles of disulfide bonds and redox chemistry in protein structure, stability, misfolding, aggregation, and the
pathogenesis of disease. By carrying out the proposed research, I will acquire crucial technical expertise in
emerging protein sequencing technologies and computational modeling and data analysis algorithms, as well as
a deeper knowledge of statistical physics, microbial physiology, and experimental evolution. Harvard University
and the greater Boston-area academic community provides a stellar environment for academic professional
development. A group of world-leading experts has been recruited as the Advisory Committee. The primary
mentor has a proven track record of training future faculty members at top research-intensive institutions. I will
take full advantage of career-development courses, workshops on inclusive teaching and building communities
of belonging, seminars on leading a research group, guidance and practice in mentorship, and a formal refresher
on responsible conduct of research. I have maintained a high level of productivity throughout my research career
(14 publications in 8 years, starting as an undergraduate), and the work arising from this award will be widely
disseminated and shared.
