Hepatitis C virus (HCV) is the second viral agent that causes the majority of chronic hepatic infections worldwide, following Hepatitis B virus (HBV) infection. HCV infection comprises several steps, from the attachment to the receptors to the delivery of the viral genetic material and replication inside the cells. Tetraspanin CD81 is a key entry factor for HCV as it accompanies the virus during attachment and internalization through clathrin-mediated endocytosis. HCV-CD81 binding takes place through the viral glycoprotein E2. We performed full-atom molecular dynamics simulations reproducing the pH conditions that occur during the viral attachment to the hepatocytes (pH 7.4) and internalization (pH 6.2-4.6). We observed that changing the pH from 7.4 to 6.2 triggers a large conformational change in the binding orientation between E2core (E2core corresponds to residues 412-645 of the viral glycoprotein E2) and CD81LEL (CD81LEL corresponds to residues 112-204 of CD81) that occurs even more rapidly at low pH 4.6. This pH-induced switching mechanism has never been observed before and could allow the virus particles to sense the right moment during the maturation of the endosome to start fusion.