Modeling and molecular dynamics of the intrinsically disordered e7 proteins from high- and low-risk types of human papillomavirus.

Cervical cancer affects millions of women worldwide each year. Most cases of cervical cancer are caused by the sexually transmitted human papillomavirus (HPV). The approximately 40 HPV types that infect the cervix are designated high- or low-risk based on their potential to lead to high-grade lesions and cancer. The HPV E7 oncoprotein is directly involved in the onset of cervical cancer and associates with the pRb protein and other cellular targets that promote cell immortalization and carcinogenesis. This is the first description of the modeling and molecular dynamics analysis of complete three-dimensional structures of high-risk (HPV types 16 and 18), low-risk (HPV type 11), and HPV type 01 E7 proteins. The models were constructed by a hybrid approach using homology (MODELLER) and ab initio (Rosetta) modeling, and the protein dynamics were simulated for 50 ns under normal pressure and temperature (NPT) conditions. The intrinsic disorder of the E7 protein sequence was assessed in silico. Complete models of E7 were obtained despite the predicted intrinsic disorder of the N-termini from the high-risk HPV types. The N-terminal domains of all of the E7 proteins studied, even those from high-risk strains, exhibited secondary structure after modeling. Trajectory analysis of E7 proteins from HPV types 16 and 18 showed higher instability in their N-terminal domains than in those of HPV types 11 and 01; however, this variation did not affect the secondary structure during the simulation. ANCHOR analysis indicated that the CR1 and CR2 regions of HPV types 16 and 18 contain possible targets for future drug-discovery studies.