Abstract
Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The hydrophobic interactions between flap and 80 s (80’s) loop residues (mainly I50-I84’ and I50’-I84) play an important role in maintaining the closed conformation of HIV-1 protease. The double mutation in Act variant weakens the hydrophobic interactions, leading to the transition from closed to semi-open conformation of apo Act. APV or DRV binds with HIV-1 protease via both hydrophobic and hydrogen bonding interactions. The hydrophobic interactions from the inhibitor is aimed to the residues of I50 (I50’), I84 (I84’), and V82 (V82’) which create hydrophobic core clusters to further stabilize the closed conformation of flaps, and the hydrogen bonding interactions are mainly focused with the active site of HIV-1 protease. The combined change in the two kinds of protease-inhibitor interactions is correlated with the observed resistance mutations. The present study sheds light on the microscopic mechanism underlying the mutation effects on the dynamics of HIV-1 protease and the inhibition by APV and DRV, providing useful information to the design of more potent and effective HIV-1 protease inhibitors.
Highlights
Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type human immunodeficiency virus (HIV)-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors
Through comparing the crystal structures of APV and DRV bound WT HIV-1 PR and its MDR variant (L63P, V82T, and I84V) and calculating their corresponding binding thermodynamics, King et al observed that the binding of the two inhibitors to the MDR variant is impaired but the impaired binding is still more favorable than those of first-generation inhibitors[36]
It was found that the I84V substitution in HIV-1 PR reduces van der Waals interactions with the inhibitors, which might account for the reduced binding affinities of both APV and DRV
Summary
Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The double mutation in Act variant weakens the hydrophobic interactions, leading to the transition from closed to semi-open conformation of apo Act. APV or DRV binds with HIV-1 protease via both hydrophobic and hydrogen bonding interactions. The hydrophobic interactions from the inhibitor is aimed to the residues of I50 (I50’), I84 (I84’), and V82 (V82’) which create hydrophobic core clusters to further stabilize the closed conformation of flaps, and the hydrogen bonding interactions are mainly focused with the active site of HIV-1 protease. The MD simulation by Hornak et al.[7] captured rare event of semi-open conformation transiting to fully open conformation These simulation studies showed that substrate-bound HIV-1 PR mainly takes closed conformation but transforms to semi-open conformation when substrate is removed. It is worth noting that the open conformations found in the abovementioned MD simulations are somehow not exactly the same: the active site is fully exposed, the flap tips are completely upward-oriented in the discovery of Hornak et al.[7] but have downward curling conformation in the discovery of Scott and Schiffer[16]
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