CAREER: CDS&E: Developing Reaction-Diffusion Models of Non-Equilibrium Virion Assembly and Budding

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Professor Margaret E. Johnson of Johns Hopkins University is supported by an award from the Chemistry of Life Processes and Chemical Theory, Models, and Computational Methods programs in the Division of Chemistry to develop and apply novel theoretical and computer simulation methods for studying virion formation, budding, and membrane remodeling leading to virion release at the cell membrane. Virions are the infective virus particles, and consist of viral DNA or RNA enclosed by a protein shell. Dr. Johnson is investigating how retroviral Gag (Group-specific Antigen) proteins perpetuate viral infection by assembling new virions on the membranes of infected cells. A molecular understanding of this critical step in the lifecycle of infectious virions can help identify targets for therapeutic intervention against viral infection. The new reaction-diffusion modeling software being developed by Dr. Johnson for this project provides the missing link coupling short molecular length-scales (chemistry) with the slow time-scales of cellular self-assembly and membrane budding (membrane mechanics). The models are being tested and iteratively refined against live cell experiments. The modeling software, graphical user interface, and rule-based model definition framework are being disseminated as open-source software and made compatible with other widely-used biophysical modeling tools, providing a transformative new approach for understanding and controlling essential cellular processes, including those involved in cell division or in viral infections. The research is closely integrated with an educational outreach program designed to improve diversity and therefore outcomes in STEM fields by teaching computer programming to Baltimore City Elementary School students. The after-school module introduces students to the power of computers in solving outstanding problems in biology and chemistry, with the goal of promoting and encouraging future careers in STEM. The goal of this project is to develop a rate-based computational model of virion formation in the cell, to determine the mechanisms of recruitment and assembly of the central retroviral Gag protein on the membrane. While the components of the final virion are known, pathways of assembly are poorly understood because the dynamics is sensitive to protein production, kinetics, membrane composition, and cellular co-factors. In this project, computer simulations of the virion components are directly compared with live-cell experiments to determine and describe the time- and space- and structure-dependent mechanisms of Gag lattice assembly in vivo, and provide a mechanism for iterative model refinement. The computational approach is made possible by the implementation of new reaction-diffusion methods for non-equilibrium assembly and membrane remodeling. The deepened understanding of virion formation and mechanistic pathways has application to predictive control over successful viral exit from infected cells, and informing strategies for therapeutic intervention. This research is contributing to the ability of the broader scientific community to study mechanisms of non-equilibrium dynamics of the cell at unprecedented resolution through public access to the powerful new methods and software being developed for the project. The research is integrated with an educational outreach program to actively promote and encourage students from diverse backgrounds in Baltimore city to consider futures in STEM by teaching them computer programming and its applications in chemistry and biology. By focusing on elementary school students, this research program will help to foster, early on, interest in STEM fields, using Professor Johnson's computational research program as a motivation and application. 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.