Catalytic Mechanism of Human T-Cell Leukemia Virus Type 1 Protease Investigated by Combined QM/MM Molecular Dynamics Simulations.

Combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations were performed to investigate the catalytic mechanism of human T-cell leukemia virus type 1 (HTLV-1) protease, a retroviral aspartic protease that is a potential therapeutic target for curing HTLV-1-associated diseases. To elucidate the proteolytic cleavage mechanism, we determined the two-dimensional free energy surfaces of the HTLV-1 protease-catalyzed reactions through various possible pathways. The free energy simulations suggest that the catalytic reactions of the HTLV-1 protease occur in the following sequential steps: (1) a proton is transferred from the lytic water to Asp32', followed by the nucleophilic addition of the resulting hydroxyl to the carbonyl carbon of the scissile bond, forming a tetrahedral oxyanion intermediate, and (2) a proton is transferred from Asp32 to the peptide nitrogen of the scissile bond, leading to the spontaneous breakage of the scissile bond.

Characterizing the protonation states of the catalytic residues in apo and substrate-bound human T-cell leukemia virus type 1 protease.

Human T-cell leukemia virus type 1 (HTLV-1) protease is an attractive target when developing inhibitors to treat HTLV-1 associated diseases. To study the catalytic mechanism and design novel HTLV-1 protease inhibitors, the protonation states of the two catalytic aspartic acid residues must be determined. Free energy simulations have been conducted to study the proton transfer reaction between the catalytic residues of HTLV-1 protease using a combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulation.