Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

10-POS Board 10 Combining In Silico and In Vitro Investigations for the Study of Selective Targeting of the Hepatitis C Virus to Its Host Chun-Chun Chang 1,2 , Hao-Jen Hsu 3 , Je-Wen Liou 1,4 . 1 Tzu Chi University, Hualien, Taiwan, 2 Tzu Chi Medical Center, Hualien, Taiwan, 3 Tzu Chi University, Hualien, Taiwan, 4 Tzu Chi University, Hualien, Taiwan. Hepatitis C virus (HCV) is one of the most important causes of human liver diseases. However, HCV infection is extremely species-specific, only human and chimpanzee can be infected. This makes the study of the HCV infection on other animal models almost impossible. Previous studies indicated that interactions between the HCV E2 glycoprotein and CD81 on the human cells are crucial for HCV infection. The main purpose of this study is to find out decisive factors for the species-specific interactions at molecular levels by employing the in silico techniques including structure model construction and molecular dynamic simulation. The binding of the HCV E2 protein on human and rat surface markers were also compared and analyzed. in vitro experiments including surface plasmon resonance measurements and cellular binding assays were followed for the validations of the in silico results. Based on the in silico studies, two binding regions on the HCV E2 loop domain were identified to be important for the interactions with CD81s, and the one of the two might be the determinant factor for the species-specificity. MM/PBSA binding free energy calculations indicated that the E2/CD81 binding process might follow a two-steps model, which involves the initial binding of human-specific region of E2 to the CD81, followed by E2 orientation change to allow the binding of the other E2 region. The amino acid sequence derived from the human-specific, stronger binding E2 region might be used as a template for the possible development of HCV inhibiting synthetic peptide drugs, and the techniques demonstrated here might be an excellent example for the study of species-specific virus/host interactions.

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