Fig 1.
Structure of HTLV-1 and HIV protease.
a, The superimposed structure of HTLV-1 (green) and HIV (pink) protease in complex with the inhibitor, Indinavir, is located in the two enzymes’ active site. The backbone RMSD value was calculated by UCSF chimera software. b, The 2D structure of Indinavir and its corresponding moieties and substitutes. c, The position of Indinavir and the residues in the active site of HIV protease. d, The position of Indinavir and the residues in the active site of HTLV-1 protease.
Fig 2.
The RMSD values of the Indinavir in the unbinding pathways in the three series of replicas for each protein-ligand complex.
a, Indinavir-HIV protease complex and b, Indinavir-HTLV-1 protease complex. Values were calculated using the crystallographic binding pose as the reference.
Fig 3.
The “out-of-equilibrium” Free Energy Landscapes (FEL) of the unbinding pathways of Indinavir.
a, b, c, from the HIV protease and, d, e, f, from the HTLV-1 protease. The stable states of Indinavir during the unbinding pathway are indicated by capital letters; Native (N), Intermediate (I1, I2), and Solvated (S).
Fig 4.
The total interaction energies of Indinavir in the unbinding pathways in the three series of replicas for each protein-ligand complex.
a, Indinavir-HIV protease complex. b, Indinavir-HTLV-1 protease complex.
Fig 5.
The contribution of each residue from both A and B chains of the proteases in the total interaction energies between Indinavir and the enzyme in the unbinding pathways.
a, Indinavir-HIV protease complex, 1st replica. b, Indinavir-HTLV-1 protease complex, 2nd replica. A and B stands for "Chain A" and "Chain B", respectively. This data is the average interaction energy of each residue during the entire SuMD simulation.
Fig 6.
The average RMSF values of residues and the RMSD values of the two proteases’ backbone atoms in three replicas.
a, RMSF values of HIV protease and, b, RMSF values of HTLV-1 protease. c, RMSD values of the backbone atoms of HIV protease and, d, RMSD values of the backbone atoms of HTLV-1 protease.
Fig 7.
The main conformational states of the flap region were acquired during the unbinding pathways of Indinavir.
a, The “out-of-equilibrium” free energy landscape and the 3D structures of HTLV-1 protease with different flap states. b, The “out-of-equilibrium” free energy landscape and the 3D structures of HIV protease with different flap states.
Fig 8.
The first step of the unbinding pathway of Indinavir.
a, Indinavir in the native state where a hydrogen bond with the Asp32 in the HTLV-1 protease keeps it stable in this state. b, the breakage of the hydrogen bond, which triggers the unbinding pathway. Both figures are frames 1153 and 1154, showing that this event needs very little time to happen. c, The distance between the OD2 atom of Asp32 and the H21 atom of Indinavir in the first 50 ns of the unbinding pathway of Indinavir-HTLV-1 complex in the 1st replica. d, The dihedral angles of the rotatable bond responsible for the rotation of the hydroxyl group of Indinavir in the first 50 ns of the unbinding pathway of Indinavir-HTLV-1 complex in the 1st replica.
Fig 9.
The interactions of Indinavir moieties with the Phe 67 and Trp98 from both chains of HTLV-1 protease during the unbinding pathway and the comparison between the RMSD values of Indinavir (Å) and the RMSD values (nm) of critical aromatic residues such as Phe67 and Trp98 in both chains during the unbinding pathways in the three replicas.
a, indanol, pyridyl, and, b, tert-butyl and benzyl moieties of Indinavir interacting with the Indinavir molecule in different states. c, The first replica of the unbinding pathway where only Trp98 from chain A showed elevated RMSD values (nm) in comparison to Indinavir RMSD values (Å). d, The second replica where the two Phe67 from both chains presented their role in comparing the Indinavir RMSD values (Å) and the residues’ RMSD values (nm). e, The third replica where Phe67 from both chains and Trp98 from chain A exhibited their role in the unbinding pathway.
Fig 10.
A comparison between the RMSF values of the Indinavir atoms during the three replicas of the unbinding pathways.
a, in the active site of the HIV protease and, b, in the active site of the HTLV-1 protease.