CAREER: A Computational Framework for Mapping Ligand Migration Channel Networks and Predicting Molecular Control Mechanisms



Proteins are fundamental elements of living organisms. They are marvelous microscopic bio-machines that function in a steady, predictable manner. Together with other elements such as DNA, they make up the basics that underlie the complexity of life. The quest to know how these bio-machines work has inspired intense scientific curiosity and imagination. Since most functions are carried out dynamically and are difficult to observe directly from experiments, computational methods have an important, irreplaceable role to play.

The objective of this proposal is to map out the ligand migration channel networks inside proteins and determine the molecular control mechanisms by which these channels are regulated dynamically. To overcome the limitations that existing methods face, the project will develop and employ a novel, efficient computational framework that draws one of its inspirations from path planning in robotics, as a ligand?s migration in a dynamic protein resembles closely a mobile robot?s navigation in a dynamic environment. The proposed approach will overcome the computational barrier by integrating efficient geometric mappings with the dynamic exploration of a protein?s structure flexibility. By taking as input the structure ensemble of a given protein, which may be composed of existing experimental structures and/or conformations generated from molecular dynamics simulations, the proposed method carries out a spatial mapping of the protein?s inner space at each conformation in the ensemble. The spatial mapping reveals the partial connectivity of the cavities and channels inside the protein. All partial maps are then merged to form a super-graph that represents the complete migration channel network that is accessible to the ligand, spatially and dynamically. The method will be applied to map out the ligand migration channel networks in a family of proteins and to study the similarities and differences in the ligand channel networks across the family, which is novel. Moreover, since the channel network is mapped for each individual conformation in the ensemble, direct correlation data between conformation changes and variations in channel sizes will be collected and analyzed to identify the key conformation changes that regulate these channels. Key residues that are responsible for the key conformation changes will then be identified. 

As a university professor, the PI has observed the prevalent lack of motivation and inspiration in undergraduate classrooms and the need for more inspired training in creative thinking among graduate students. To address these pressing needs, the education objectives of this proposal are: i) to infuse scientific curiosity and motivation into the undergraduate classrooms, ii) to train motivated undergraduate and graduate students to become creative thinkers, and iii) to spread the excitement of learning and discovery to the community, to junior high and high school students. The PI believes that the inter-disciplinary nature of his research should provide invaluable resources to engender scientific curiosity and to inspire cross-disciplinary creative thinking among the students. 

Intellectual merits: the project will develop a novel computational framework for mapping ligand migration channel networks. Upon completion of this project, it is expected that a clear understanding of the control mechanism by which ligand migration channel networks are regulated will have been developed. Key control residues, or molecular switches, will be identified. The precise roles of protein motions and dynamics will be delineated. Such an understanding of functional mechanisms can be used to interpret the existing experimental results or make new predictions that can guide future experiments.

Broader impacts: the proposed research activities will be closely integrated with education activities. The PI?s interdisciplinary research will be used to cultivate scientific curiosity and cross-disciplinary creative thinking among students, especially for women, underserved minorities and the disabled. The project will create ample opportunities for undergraduate and graduate students to participate in research and to be trained to become creative thinkers. The research results will be broadly disseminated through journal publications and conference presentations. The computational framework developed in this project will provide the scientific community with an invaluable tool that can be adapted to study the molecular control mechanisms of many other bio-molecules.

2010-03-01 to 2016-02-29
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