Resolving the Structure of Viral Genomes with Atomic Precision

Aleksei Aksimentiev, University of Illinois at Urbana-Champaign

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Aleksei Aksimentiev, Christopher Maffeo, Manish Shankla, Han-Yi Chou, David Winogradoff, Shidi Zhao, Himanshu IMANSHU Joshi, Kumar Sarthak, Kush Coshic, Adnan Choudhary, Lauren Quednau

Viruses are omnipresent, diverse and potentially lethal biological systems that our bodies encounter every day in copious quantities without us taking notice. The reason is simple: viruses are incredibly small and can evade our defense systems. The essence of each virus is its genome, a biological program written using letters of the genetic alphabet. The genome is protected from the outside world by a protein shell—a viral capsid—until the conditions are met for viral invasion, whereby the genome is released from its protective shell into a host cell, initiating a new cycle of infection. This project will explore a new route for development of antiviral therapeutics by determining the physical organization of the viral genome inside its protective shell. Using our recently developed multi-resolution molecular dynamics approach calibrated against cryo-electron microscopy, micro-calorimetry and single-molecule data, we will obtain the first atomically-precise structural models of genomes conned inside bacteriophage lambda, hepatitis B and adeno-associated virus capsids. The models will be used to identify structural motifs specific to each virus that can present targets for drugs that irreversibly crosslink DNA to itself or to proteins of the capsid in a manner that prevents genome release into host cells. Because the project requires multiple all-atom simulations of entire viral particles, Blue Waters is one of a few supercomputers in the world suitable for accomplishing this project. Successful completion of this project will set the stage for follow-up studies that will investigate genome organization in larger and more complex human viruses.