Differential Flap Dynamics in Wild-Type and a Drug Resistant Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation

Cai, Yufeng; Yilmaz, Neşe Kurt; Myint, Wazo; Ishima, Rieko; Schiffer, Celia A.

doi:10.1021/ct300076y

Cited by 60 publications

(99 citation statements)

References 54 publications

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“…Fig. 8 shows plots of S 2 values determined for apo-inactive constructs Bi, PR5i, and AEi The results of Bi are similar to those obtained previously for a related subtype B construct called PMPR (19,21,31,59,64). Consistent with earlier findings, S 2 values plotted as a function of residue number (Fig.…”

supporting

confidence: 81%

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The Role of Select Subtype Polymorphisms on HIV-1 Protease Conformational Sampling and Dynamics

Huang

Britto

Kear-Scott

et al. 2014

Journal of Biological Chemistry

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Background: HIV-1 protease is an essential enzyme for HIV maturation. Results: Select and naturally occurring polymorphisms alter the conformational sampling and backbone dynamics of HIV-1 protease. Conclusion: These mutations lead to an alternative flap ensemble that we suspect is a curled flap orientation. Significance: The mechanism of distal mutations on drug resistance is unclear, but altered dynamics and conformational equilibria likely play key roles.

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supporting

confidence: 81%

“…curling upon interaction with inhibitors (31). To gain insight regarding the origin of this additional curled flap conformation, a combination of four naturally occurring polymorphisms common in the sequences of subtypes A, F, and C were introduced into subtype B.…”

Section: Hiv-1 Protease (Hiv-1 Pr)mentioning

confidence: 99%

The Role of Select Subtype Polymorphisms on HIV-1 Protease Conformational Sampling and Dynamics

Huang

Britto

Kear-Scott

et al. 2014

Journal of Biological Chemistry

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“…Although crystal structures provide key insights, alteration of dynamic behavior, not captured by static structures, is emerging as an additional contribution to mechanisms of drug resistance (37,38). We found that drug resistance mutations in the protease or in the native substrate disturbed the active site dynamics, which was restored in all coevolved complexes bearing complementary mutations in both the protease and the substrate.…”

Section: Discussionmentioning

confidence: 84%

Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease

Özen

Lin

Yilmaz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Drug resistance mutations in response to HIV-1 protease inhibitors are selected not only in the drug target but elsewhere in the viral genome, especially at the protease cleavage sites in the precursor protein Gag. To understand the molecular basis of this proteasesubstrate coevolution, we solved the crystal structures of drug resistant I50V/A71V HIV-1 protease with p1-p6 substrates bearing coevolved mutations. Analyses of the protease-substrate interactions reveal that compensatory coevolved mutations in the substrate do not restore interactions lost due to protease mutations, but instead establish other interactions that are not restricted to the site of mutation. Mutation of a substrate residue has distal effects on other residues' interactions as well, including through the induction of a conformational change in the protease. Additionally, molecular dynamics simulations suggest that restoration of active site dynamics is an additional constraint in the selection of coevolved mutations. Hence, protease-substrate coevolution permits mutational, structural, and dynamic changes via molecular mechanisms that involve distal effects contributing to drug resistance.HIV-1 protease | drug resistance | coevolution | crystallography | active site dynamics

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“…Furthermore, experimental studies have shown that there is a relationship between conformational sampling and drug resistance in HIV-PR (Cai et al, 2014;Cai et al 2012Foulkes-Murzycki et al, 2013Gibbs, 2014 andde Vera et al, 2013). Therefore, understanding functional dynamics of the flaps of HIV-PR is of great importance to the development of new HIV-PR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Unraveling HIV protease flaps dynamics by Constant pH Molecular Dynamics simulations

Soares

Tôrres

Silva

et al. 2016

Journal of Structural Biology

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a b s t r a c tThe active site of HIV protease (HIV-PR) is covered by two flaps. These flaps are known to be essential for the catalytic activity of the HIV-PR, but their exact conformations at the different stages of the enzymatic pathway remain subject to debate. Understanding the correct functional dynamics of the flaps might aid the development of new HIV-PR inhibitors. It is known that, the HIV-PR catalytic efficiency is pHdependent, likely due to the influence of processes such as charge transfer and protonation/deprotonation of ionizable residues. Several Molecular Dynamics (MD) simulations have reported information about the HIV-PR flaps. However, in MD simulations the protonation of a residue is fixed and thus it is not possible to study the correlation between conformation and protonation state. To address this shortcoming, this work attempts to capture, through Constant pH Molecular Dynamics (CpHMD), the conformations of the apo, substrate-bound and inhibitor-bound HIV-PR, which differ drastically in their flap arrangements. The results show that the HIV-PR flaps conformations are defined by the protonation of the catalytic residues Asp25/Asp25 0 and that these residues are sensitive to pH changes. This study suggests that the catalytic aspartates can modulate the opening of the active site and substrate binding.

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Differential Flap Dynamics in Wild-Type and a Drug Resistant Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation

Cited by 60 publications

References 54 publications

The Role of Select Subtype Polymorphisms on HIV-1 Protease Conformational Sampling and Dynamics

The Role of Select Subtype Polymorphisms on HIV-1 Protease Conformational Sampling and Dynamics

Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease

Unraveling HIV protease flaps dynamics by Constant pH Molecular Dynamics simulations

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