Molecular modeling study on the resistance mechanism of HCV NS3/4A serine protease mutants R155K, A156V and D168A to TMC435

► Resistance mechanism of three main HCV NS3/4A mutants to TMC435 were investigated. ► R155K and D168A mutations break the intermolecular salt bridges network. ► A156V mutation disrupts the two substrate-like intermolecular hydrogen bonds. ► The three key mutations make NS3A change the induced-fit binding conformation.