Bacteriophages are viruses that infect bacteria and they are the most abundant organisms on our planet. They are also sophisticated machines that exploit mechanics as vividly illustrated by bacteriophage T4 which injects its DNA into a host through an amazing protein machine. This research will answer fundamental questions regarding how the injection machinery works using novel computational modeling methods. The computational models will expose details of the entire, highly dynamic injection process by advancing modeling and simulation methods for longer time and space scales and with greater detail than current approaches. This research, which lies at the intersection of mechanical engineering, molecular biophysics and computational science, has direct implications to advances in nanotechnologies which aim to harness viral machinery for useful purposes for human health.
The research will combine continuum models and large scale all-atom molecular dynamics simulations to arrive at a multi-scale model that captures the dynamics of the T4 injection machinery. In particular, the multi-scale model will emerge from a novel coupling of local (atomistic) and global (continuum) representations of the major protein domains of the injection machinery, including the flexible sheath structure which powers injection, the central tail tube that penetrates the host (E. coli), and the modulating effects due to hydrodynamic forces on the viral capsid (head) and the interaction forces of the host on the tip of the tail tube. Simulations based on this multi-scale model will reveal the biological time scale of injection, generate dynamical pathways for tail contraction, explain the stored energy mechanism driving injection, and predict the forces responsible for driving the tail into the host cell. Individually, these represent major contributions in understanding the science of virus infection at a mechanistic level. These contributions may also enable future advances in the use of viruses in nanotechnology applications ranging from gating, sensing, translocation, peptide display, and phage therapy. In addition, this project will positively impact the education of two doctoral students who will create the multi-scale model and a team of undergraduate students who will construct a working mechanical model of the T4 injection machinery. The project will also engage the broader public by featuring results at scientific workshops, educating graduate students and postdocs in the Mathematical and Computational Biology Gateway Program at UC-Irvine, conducting engineering-themed lessons at Adams Academy in Ypsilanti, Michigan, and disseminating simulation results through the Computational Modeling Facility at UC-Irvine and to two partner institutions with large URM student populations.
