RUI: Investigation of the structure and dynamics of type IV pilus filaments using all-atom and coarse-grained molecular dynamics

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This project will use advanced computational approaches to better understand the biomechanical properties of a protein filament that has applications ranging from bionanotechnology to cell motion and bacterial infection. Bacteria and archaea can adhere to surfaces using long, "sticky" filaments that protrude from their cell membranes called type IV pili (T4P). These filaments, which are made of thousands of copies of a protein called pilin, are incredibly strong, yet simultaneously extremely flexible. For example, a single bacterial T4P filament can support up to 10,000 times a bacterium's body weight, and T4P can be stretched to three times their original length without breaking. This project will use a computational approach known as molecular dynamics simulation to investigate the structure and dynamics of T4P filaments. Using this computational approach, simulated forces will be applied to T4P filaments to probe how they respond to being stretched, which will allow the identification of interactions that provide T4P with their great strength. The insights about T4P that will result from this work will inform applications in bionanotechnology, the role that T4P play in bacterial adhesion and motion, and will expand our general knowledge about protein filaments. Furthermore, this project will provide significant training to undergraduate students in a highly cross-disciplinary area of research at the interface of biology, physics, chemistry, and computer science. It will also develop computational learning modules and incorporate them into the undergraduate science curriculum to train students in the computational methods that are increasingly important in all scientific fields.This project uses a computation/theory-led approach to: (1) investigate the dynamics of T4P filaments from three organisms, N. gonorrhoeae, N. meningitidis, and P. aeruginosa, at the all-atom level of resolution using all-atom molecular dynamics simulation, and (2) develop coarse-grained models to study the structural properties of T4P filaments, including the structural transition that occurs for T4P under external force. This comprehensive, multi scale computational approach will provide insights into the strength and dynamics of T4P across multiple length and time scales relevant to T4P function, and importantly will bridge the gap in knowledge that currently exists between the experimental and theoretical understanding of the biomechanics of T4P filaments. Specifically, all-atom simulations will be used to characterize T4P structural heterogeneity and to identify the most important interactions between pilin subunits for maintaining T4P structural integrity in the initial stages of the polymorphic transition that T4P exhibit under the application of external force. External forces will be applied to T4P using steered molecular dynamics protocols. Additionally, all-atom and coarse-grained simulations will be used in combination to determine important T4P filament properties such as the Young's modulus, persistence length, and torsional rigidity. Finally, coarse-grained simulations of T4P filaments under force will allow for the development of the first model of the fully force-transitioned state of a T4P filament, providing unprecedented molecular-scale insights into how the filament changes shape at the molecular scale. The coarse-grained T4P model developed in this project will act as a starting model for bridging from the atomistic scale to the scale of cellular biology. This project will provide novel insights into T4P biomechanics, aid in the fundamental understanding of the role of T4P in prokaryotes, and improve understanding of the plasticity of helical biopolymers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.