Conformational Dynamics and Disorder of HPV-16 E6

Abstract

Persistent infection with high-risk human papillomaviruses drives oncogenesis through the E6 oncoprotein (16E6), which engages diverse host partners through its LxxLL-binding groove. How partner-free 16E6 behaves in solution remains poorly characterized. Here, we combine 35 μs of all-atom molecular dynamics, well-tempered metadynamics, Markov state modeling, and BioEmu ensemble generation to describe apo-16E6. Across all four approaches, the interdomain linker E6HL and the C-terminal tail emerge as intrinsically disordered regions whose dynamics are coupled with LxxLL-groove geometry. A Markov state model resolves open and closed conformational states that differ in E6HL helicity, C-terminal tail extension and groove aperture, interconverting on time scales of at least tens of microseconds. Metadynamics samples three interdomain-separation regions extending to approximately 36 Å, each recurring across the three Q107 rotamers, and BioEmu generates conformers from compact to highly extended. These results are consistent with coupled linker and tail fluctuations underlying a disorder-to-order transition upon partner binding and motivate ensemble-aware inhibitor discovery.