ITR-ASE-Sim: Inhomogeneously Resolved Simulation of Protein Assembly Dynamics

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This award is cofunded by the Division of Materials Research and the Chemistry Division. It was made on a proposal submitted to the Division of Materials Research under the Information Technology Research solicitation NSF-04-012. Research activities covered by this award fall under the National Priority Area, "Advances in Science and Engineering," and the Technical Focus Area, "Innovation in Computational Modeling or Simulation in Research." This award supports computational research and education to develop simulation methods and use them to elucidate the role of chaperonins in protein folding.In the last ten years, chaperonins have become one of the most actively studied classes of biomolecules. A detailed understanding of how they assist protein folding in living cells will enable opportunities for engineering cells for optimal expression of desired polypeptides and even designing agents to combat diseases caused by protein agents. This project involves large-scale molecular simulation to answer specific questions regarding the mechanisms by which the E. Coli GroEL/GroES chaperonin protein complex assists the folding of proteins. Transition path sampling Monte-Carlo (TPS) will be combined with new inhomogeneous resolution descriptions to enable statistically valid predictions of rates and mechanisms using a minimum of detailed information as input. In the paradigm of inhomogeneous molecular simulation, the domain is divided into (i) one or more atomically resolved regions of interest, and (ii) a much larger surrounding systematically coarsened subdomain. The coarsened descriptions reduce the computational effort over atomically resolved systems, while the regions of interest represent the system's specificity up to a desired level. The project has two broad phases, devoted to answering the questions: (1) Is binding to GroEL correlated with the destruction of secondary and tertiary structure in misfolded proteins? (2) What are the intrinsic energy barriers associated with large-scale conformational changes of GroEL upon conversion to its active state? The broader impacts of this work include: developing a course module on chaperonin-assisted protein folding for a graduate course in biological physics; developing a graduate level course on molecular simulation which will incorporate major new techniques of systematic molecular coarse graining; ?involving undergraduates in research recruited with an eye to including underrepresented groups; and conducting workshops on presentation preparation and delivery skills, primarily to benefit students. Undergraduate and graduate student researchers on this project will be encouraged to present their work at national conferences. %%%This award is cofunded by the Division of Materials Research and the Chemistry Division. It was made on a proposal submitted to the Division of Materials Research under the Information Technology Research solicitation NSF-04-012. Research activities covered by this award fall under the National Priority Area, "Advances in Science and Engineering," and the Technical Focus Area, "Innovation in Computational Modeling or Simulation in Research." This award supports computational research and education at the interface with biology. The PI will use large-scale simulation techniques in an innovative way to study the role of biomolecules known as chaperonins in the process whereby long chain-like protein molecules fold on themselves to achieve a configuration of atoms that enables specific biochemical functions. In the last ten years, chaperonins have become one of the most actively studied classes of biomolecules. A detailed understanding of they assist protein folding in living cells will enable opportunities for engineering cells for optimal expression of desired polypeptides and even designing agents to combat diseases caused by protein agents. The PI will use simulation techniques to focus on specific issues regarding the mechanisms by which the E. Coli GroEL/GroES chaperonin protein complex assists the folding of proteins. The broader impacts of this work include: developing a course module on chaperonin-assisted protein folding for a graduate course in biological physics; developing a graduate level course on molecular simulation which will incorporate major new techniques of systematic molecular coarse graining; ?involving undergraduates in research recruited with an eye to including underrepresented groups; and conducting workshops on presentation preparation and delivery skills, primarily to benefit students. Undergraduate and graduate student researchers on this project will be encouraged to present their work at national conferences. ***