Purdue University Graduate School
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Flexible and Data-Driven Modeling of 3D Protein Complex Structures

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posted on 2023-11-30, 07:48 authored by Charles W ChristofferCharles W Christoffer

Proteins and their interactions with each other, with nucleic acids, and with other molecules are foundational to all known forms of life. The three-dimensional structures of these interactions are an essential component of a comprehensive understanding of how they function. Molecular-biological hypothesis formulation and rational drug design are both often predicated on a particular structure model of the molecule or complex of interest. While experimental methods capable of determining atomic-detail structures of molecules and complexes exist, such as the popular X-ray crystallography and cryo-electron microscopy, these methods require both laborious sample preparation and expensive instruments with limited throughput. Computational methods of predicting complex structures are therefore desirable if they can enable cheap, high-throughput virtual screening of the space of biological hypotheses. Many common biomolecular contexts have largely been blind spots for predictive modeling of complex structures. In this direction, docking methods are proposed to address extreme conformational change, nonuniform environments, and distance-geometric priors. Flex-LZerD deforms a flexible protein using a novel fitting procedure based on iterated normal mode decomposition and was shown to construct accurate complex models even when an initial input subunit structure exhibits extreme conformational differences from its bound state. Mem-LZerD efficiently constrains the docking search space by augmenting the geometric hashing data structure at the core of the LZerD algorithm and enabled membrane protein complexes to be efficiently and accurately modeled. Finally, atomic distance-based approaches developed during modeling competitions and collaborations with wet lab biologists were shown to effectively integrate domain knowledge into complex modeling pipelines.


Purdue University Molecular Biophysics Training Program

National Institute of General Medical Sciences

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Degree Type

  • Doctor of Philosophy


  • Computer Science

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Daisuke Kihara

Additional Committee Member 2

Alex Pothen

Additional Committee Member 3

Majid Kazemian

Additional Committee Member 4

Ahmed Qureshi

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