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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
43
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.