Strained template under the thumbs - How reverse transcriptase of human immunodeficiency virus type 1 moves along its template

In retroviruses, such as human immunodeficiency virus type 1 (HIV-1), the reverse transcriptase (RT) copies single-stranded viral RNA into complementary DNA, which is then used as a template for synthesis of the second DNA strand. The resulting double-stranded DNA is integrated into the host genome. How RT translocates on the different templates is the subject of this study. We have developed a theoretical model for RT translocation during processive DNA synthesis. The model is based on the assumption that there are two template-binding sites, namely the helix clamps, located in the thumb subdomains of RT subunits p66 and p51. Flexibility of the p66 thumb provides undisrupted template-binding during polymerase translocation. Coordinated association and dissociation of the template at the thumbs, triggered by nucleotide incorporation, is assumed, which ensures template contact with at least one subdomain throughout translocation. We suggest that coordination between the sites is effected by stress in the template region located between the thumbs. Translocation of HIV-1 RT proceeds continuously but with different processivities on RNA and DNA templates. These findings are explained in detail by the proposed model.