Effects of Drug-resistant Mutations on the Dynamic Properties of HIV-1 Protease and Inhibition by Amprenavir and Darunavir

Overview

Journal Sci Rep

Specialty Science

Date 2015 May 28

PMID 26012849

Citations 20

Authors

Yuqi Yu

Jinan Wang

Qiang Shao

Jiye Shi

Weiliang Zhu

Affiliations

Soon will be listed here.

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.

Citing Articles

Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors.

Ur Rehman M, Chuntakaruk H, Amphan S, Suroengrit A, Hengphasatporn K, Shigeta Y ACS Bio Med Chem Au. 2024; 4(5):242-256.

PMID: 39431267 PMC: 11487539. DOI: 10.1021/acsbiomedchemau.4c00040.

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors.

Chuntakaruk H, Hengphasatporn K, Shigeta Y, Aonbangkhen C, Lee V, Khotavivattana T Sci Rep. 2024; 14(1):3639.

PMID: 38351065 PMC: 10864397. DOI: 10.1038/s41598-024-53940-1.

The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation.

Shabanpour Y, Sajjadi S, Behmard E, Abdolmaleki P, Keihan A Front Mol Biosci. 2022; 9:927373.

PMID: 36046605 PMC: 9420863. DOI: 10.3389/fmolb.2022.927373.

Structural and functional insights into the DNA damage-inducible protein 1 (Ddi1) from protozoa.

Asaithambi K, Biswas I, Suguna K Curr Res Struct Biol. 2022; 4:175-191.

PMID: 35677776 PMC: 9168383. DOI: 10.1016/j.crstbi.2022.05.003.

Predicted antiviral drugs Darunavir, Amprenavir, Rimantadine and Saquinavir can potentially bind to neutralize SARS-CoV-2 conserved proteins.

Halder U J Biol Res (Thessalon). 2021; 28(1):18.

PMID: 34344455 PMC: 8331326. DOI: 10.1186/s40709-021-00149-2.

References

Duan Y, Wu C, Chowdhury S, Lee M, Xiong G, Zhang W . A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem. 2003; 24(16):1999-2012. DOI: 10.1002/jcc.10349. View

Foulkes-Murzycki J, Rosi C, Yilmaz N, Shafer R, Schiffer C . Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease. ACS Chem Biol. 2012; 8(3):513-8. PMC: 3805267. DOI: 10.1021/cb3006193. View

Scott W, Schiffer C . Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance. Structure. 2001; 8(12):1259-65. DOI: 10.1016/s0969-2126(00)00537-2. View

Lange O, Grubmuller H . Generalized correlation for biomolecular dynamics. Proteins. 2005; 62(4):1053-61. DOI: 10.1002/prot.20784. View

Tozzini V, Trylska J, Chang C, McCammon J . Flap opening dynamics in HIV-1 protease explored with a coarse-grained model. J Struct Biol. 2006; 157(3):606-15. DOI: 10.1016/j.jsb.2006.08.005. View

Freedberg D, Ishima R, Jacob J, Wang Y, Kustanovich I, Louis J . Rapid structural fluctuations of the free HIV protease flaps in solution: relationship to crystal structures and comparison with predictions of dynamics calculations. Protein Sci. 2002; 11(2):221-32. PMC: 2373438. DOI: 10.1110/ps.33202. View

Wang Y, Freedberg D, Yamazaki T, Wingfield P, Stahl S, Kaufman J . Solution NMR evidence that the HIV-1 protease catalytic aspartyl groups have different ionization states in the complex formed with the asymmetric drug KNI-272. Biochemistry. 1996; 35(31):9945-50. DOI: 10.1021/bi961268z. View

Duan L, Tong Y, Mei Y, Zhang Q, Zhang J . Quantum study of HIV-1 protease-bridge water interaction. J Chem Phys. 2007; 127(14):145101. DOI: 10.1063/1.2770720. View

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

10.

Liu F, Kovalevsky A, Tie Y, Ghosh A, Harrison R, Weber I . Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir. J Mol Biol. 2008; 381(1):102-15. PMC: 2754059. DOI: 10.1016/j.jmb.2008.05.062. View

11.

Cai Y, Myint W, Paulsen J, Schiffer C, Ishima R, Yilmaz N . Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease. J Chem Theory Comput. 2014; 10(8):3438-3448. PMC: 4132871. DOI: 10.1021/ct4010454. View

12.

Cai Y, Schiffer C . Decomposing the energetic impact of drug resistant mutations in HIV-1 protease on binding DRV. J Chem Theory Comput. 2010; 6(4):1358-1368. PMC: 2882104. DOI: 10.1021/ct9004678. View

13.

King N, Prabu-Jeyabalan M, Nalivaika E, Wigerinck P, de Bethune M, Schiffer C . Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Virol. 2004; 78(21):12012-21. PMC: 523255. DOI: 10.1128/JVI.78.21.12012-12021.2004. View

14.

Mittal S, Cai Y, Nalam M, Bolon D, Schiffer C . Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease. J Am Chem Soc. 2012; 134(9):4163-8. PMC: 3391577. DOI: 10.1021/ja2095766. View

15.

Hoover . Canonical dynamics: Equilibrium phase-space distributions. Phys Rev A Gen Phys. 1985; 31(3):1695-1697. DOI: 10.1103/physreva.31.1695. View

16.

Meher B, Wang Y . Interaction of I50V mutant and I50L/A71V double mutant HIV-protease with inhibitor TMC114 (darunavir): molecular dynamics simulation and binding free energy studies. J Phys Chem B. 2012; 116(6):1884-900. PMC: 3288396. DOI: 10.1021/jp2074804. View

17.

Bussi G, Donadio D, Parrinello M . Canonical sampling through velocity rescaling. J Chem Phys. 2007; 126(1):014101. DOI: 10.1063/1.2408420. View

18.

Cai Y, Yilmaz N, Myint W, Ishima R, Schiffer C . Differential Flap Dynamics in Wild-type and a Drug Resistant Variant of HIV-1 Protease Revealed by Molecular Dynamics and NMR Relaxation. J Chem Theory Comput. 2012; 8(10):3452-3462. PMC: 3491577. DOI: 10.1021/ct300076y. View

19.

Nalam M, Ali A, Altman M, Reddy G, Chellappan S, Kairys V . Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance. J Virol. 2010; 84(10):5368-78. PMC: 2863851. DOI: 10.1128/JVI.02531-09. View

20.

Tzoupis H, Leonis G, Mavromoustakos T, Papadopoulos M . A Comparative Molecular Dynamics, MM-PBSA and Thermodynamic Integration Study of Saquinavir Complexes with Wild-Type HIV-1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V Single Mutants. J Chem Theory Comput. 2015; 9(3):1754-64. DOI: 10.1021/ct301063k. View