Viruses that replicate their own genomes need two enzymatic activities at the replication fork. They must unwind the DNA double helix and make the short RNA primers that start each new strand. Herpesviruses do both with a single machine: the helicase–primase complex. It is built from a helicase, a primase, and an accessory subunit and this assembly is essential for viral replication and a validated antiviral target. Inhibitor-bound structures exist for one herpesvirus, but for most family members the architecture of the machine and the basis of inhibitor sensitivity remain open questions.

Our lab studies molecular machines of human and viral DNA replication by cryo-EM. In this project, the student will build and refine atomic models of viral helicase–primase complexes into experimental cryo-EM maps, using AI-based structure prediction to generate starting models. These models will then be refined and validated in using standard structural biology tools. The refined models will show how the helicase and primase modules are arranged, trace the bound nucleic acid, and map the inhibitor-binding pocket, including the positions of known resistance mutations.

The work is mostly computational, but it sits inside an active experimental program. There is room to learn the bench side as well: expressing and purifying the subunits, reconstituting the complex, running activity assays, and preparing cryo-EM grids. How the time is split between modeling and bench work depends on the student's background and interests. No prior cryo-EM experience is needed. 

• Atomic models of one or more viral helicase–primase complexes refined into experimental cryo-EM maps.
• Full model validation: fit-to-map metrics, geometry and clash checks, per-residue confidence.
• Structural analysis of the nucleic acid binding path and the inhibitor-binding region, with resistance mutations mapped.
• Optional bench contribution: protein expression and purification, complex reconstitution, biochemical assays, cryo-EM sample preparation.