The role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics

Chordia, Poorvi; Dewdney, Tamaria G.; Keusch, Bradley; Kuiper, Benjamin; Ross, K.; Kovari, Iulia A.; MacArthur, Rodger D.; Salimnia, Hossein; Kovari, Ladislau C.

doi:10.15190/d.2014.19

Cited by 2 publications

(3 citation statements)

References 21 publications

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“…The systems were placed in a TIP3P 5 Å water box and neutralized with magnesium chloride. MD simulations were performed as previously described [5] using NAMD [21] V. 2.9.…”

Section: Methodsmentioning

confidence: 99%

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The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops

Kuiper

Keusch

Dewdney

et al. 2015

Biochemistry and Biophysics Reports

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HIV-1 protease (PR) is a 99 amino acid protein responsible for proteolytic processing of the viral polyprotein – an essential step in the HIV-1 life cycle. Drug resistance mutations in PR that are selected during antiretroviral therapy lead to reduced efficacy of protease inhibitors (PI) including darunavir (DRV). To identify the structural mechanisms associated with the DRV resistance mutation L33F, we performed X-ray crystallographic studies with a multi-drug resistant HIV-1 protease isolate that contains the L33F mutation (MDR769 L33F). In contrast to other PR L33F DRV complexes, the structure of MDR769 L33F complexed with DRV reported here displays the protease flaps in an open conformation. The L33F mutation increases noncovalent interactions in the hydrophobic pocket of the PR compared to the wild-type (WT) structure. As a result, L33F appears to act as a molecular anchor, reducing the flexibility of the 30s loop (residues 29–35) and the 80s loop (residues 79–84). Molecular anchoring of the 30s and 80s loops leaves an open S1/S1′ subsite and distorts the conserved hydrogen-bonding network of DRV. These findings are consistent with previous reports despite structural differences with regards to flap conformation.

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“…The systems were placed in a TIP3P 5 Å water box and neutralized with magnesium chloride. MD simulations were performed as previously described [5] using NAMD [21] V. 2.9.…”

Section: Methodsmentioning

confidence: 99%

“…These mutations confer resistance to all FDA approved PIs ( http://hivdb.stanford.edu /) [4] . Molecular dynamics simulations with these isolates showed altered PR flap dynamics [5] .…”

Section: Introductionmentioning

confidence: 97%

The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops

Kuiper

Keusch

Dewdney

et al. 2015

Biochemistry and Biophysics Reports

Self Cite

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“…From the RMSD plot, it can be seen that all the I36T↑T/inhibitor complexes showed an increase in RMSD throughout the MD simulation, leading to the assumption that the polymorphisms found in the I36T↑T protease causes increased flexibility as compared to the subtype B protease on which the starting structures and position of inhibitors was modelled. The RMSF plots show areas of high flexibility; however, these areas do not correspond to the site of the mutations or insertion; therefore, we conclude that these polymorphisms do not alter the flexibility of their immediate location but rather have a long‐range effect on the flexibility of other residues.…”

Section: Resultsmentioning

confidence: 99%

Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

et al. 2016

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In this work, have investigated the binding affinities of nine FDA-approved protease inhibitor drugs against a new HIV-1 subtype C mutated protease, I36T↑T. Without an X-ray crystal structure, homology modelling was used to generate a three-dimensional model of the protease. This and the inhibitor models were employed to generate the inhibitor/I36T↑T complexes, with the relative positions of the inhibitors being superimposed and aligned using the X-ray crystal structures of the inhibitors/HIV-1 subtype B complexes as a reference. Molecular dynamics simulations were carried out on the complexes to calculate the average binding free energies for each inhibitor using the molecular mechanics generalized Born surface area (MM-GBSA) method. When compared to the binding free energies of the HIV-1 subtype B and subtype C proteases (calculated previously by our group using the same method), it was clear that the I36T↑T proteases mutations and insertion had a significant negative effect on the binding energies of the non-pepditic inhibitors nelfinavir, darunavir and tipranavir. On the other hand, ritonavir, amprenavir and indinavir show improved calculated binding energies in comparison with the corresponding data for wild-type C-SA protease. The computational model used in this study can be used to investigate new mutations of the HIV protease and help in establishing effective HIV drug regimes and may also aid in future protease drug design.

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The role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics

Cited by 2 publications

References 21 publications

The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops

The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops

Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

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