With support from the Emerging Models and Technologies for Computation Program (EMT), the researchers at University of the Sciences in Philadelphia (USP) plan to develop a novel computational approach for studying complex biological systems. In this proposal we plan on studying a small part of the signal transduction pathway used in chemotaxis (the movement in response to a chemical). Our approach combines bioinformatics-assisted molecular modeling techniques with a novel coarse grain (CG) molecular dynamics method. The proposed work includes three major parts. First, new CG protein models and parameters will be developed to compliment the recently created CG dynamics program and CG lipid bilayer models. Second, a complex structural framework of a transmembrane signal transduction system, the bacterial chemotaxis protein complexes, will be constructed by utilizing a variety of bioinformatics and molecular modeling techniques such as primary sequence analysis, homology modeling, docking and random loop building. Third, the complex structural framework will be mapped into the CG representation of the protein and lipid bilayer. The CG simulations at the millisecond scale will be carried out to characterize structural, conformational and dynamic properties of the bacterial chemotaxis system.
The major advantage of CG dynamics simulation is that the computational demands are approximately four orders of magnitudes less than the conventional all-atom molecular dynamics, at the expense of some atomistic details. It will thus enable dynamics simulations of a biological transmembrane system to the milliseconds timescale for the first time. Since many biological events of interest (e.g. signal transduction) happen on this time scale, the proposed simulations will significantly enhance our computational capabilities in solving complex biological problems. Through the simulation, specific conformational changes as part of the signaling process in the cytoplasmic domain, which remains unknown, will be elucidated. While the results are important in themselves, they will serve to demonstrate the power of these techniques, and allow for extensions into other fields with temporal and spatial limitations. The results will accelerate the research on membrane proteins and by extension, have a broad and significant impact in a wide number of research areas, including computational biology, chemistry, biochemistry, physical chemistry, as well as related fields such as medicine, biology and physics.
The proposed work will be carried out by collaboration of a group of experts from different areas of computational biology and chemistry at USP. Graduate students from different disciplines (bioinformatics, chemistry, computer science) will be trained and perform many of the proposed studies, thus the grant will promote teaching and training of students and learning across scientific disciplines. Additionally, the results of the research will be broadly disseminated by publication in peer-reviewed journals, at national and international conferences, on web sites and in the classrooms. The computer programs generated as well as parameters developed will be shared freely to benefit academic and non-commercial researches, via internet and public licensing.
