Analysis of the structure of HIV-1 protease complexed with a hexapeptide inhibitor. Part II: Molecular dynamic studies of the active site region

Geller, Maciej; Miller, Maria; Swanson, Stanley M.; Maizel, Jacob V.

doi:10.1002/(sici)1097-0134(199702)27:2<195::aid-prot5>3.0.co;2-f

Cited by 15 publications

(4 citation statements)

References 25 publications

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“…The water molecules were added to the binding site of 1hvs because all the water molecules were absent in the experimental structure. Protein protonation states were modeled as in the related HIV-1 protease MD simulation study [56]. All protein residues were modeled in their charged state except for one of the two aspartic acid groups (Asp 25 and Asp 25') in the active site since previous studies [57-59] have shown that at least one of these two aspartic acids is protonated.…”

Section: Methodsmentioning

confidence: 99%

Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations

Jenwitheesuk

Samudrala

2003

BMC Struct Biol

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BackgroundThe accurate prediction of enzyme-substrate interaction energies is one of the major challenges in computational biology. This study describes the improvement of protein-ligand binding energy prediction by incorporating protein flexibility through the use of molecular dynamics (MD) simulations.ResultsDocking experiments were undertaken using the program AutoDock for twenty-five HIV-1 protease-inhibitor complexes determined by x-ray crystallography. Protein-rigid docking without any dynamics produced a low correlation of 0.38 between the experimental and calculated binding energies. Correlations improved significantly for all time scales of MD simulations of the receptor-ligand complex. The highest correlation coefficient of 0.87 between the experimental and calculated energies was obtained after 0.1 picoseconds of dynamics simulation.ConclusionOur results indicate that relaxation of protein complexes by MD simulation is useful and necessary to obtain binding energies that are representative of the experimentally determined values.

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Section: Methodsmentioning

confidence: 99%

Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations

Jenwitheesuk

Samudrala

2003

BMC Struct Biol

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“…Nevertheless, the location of protons in the active site may determine the reaction path. This problem has been addressed before ex-perimentally (Hyland et al, 1991a;Ido et al, 1991;Smith et al, 1996;Yamazaki et al, 1994;Wang et al, 1996) and theoretically (Harte and Beveridge, 1993;Chatfield and Brooks, 1995;Geller et al, 1997;Trylska et al, 1999;Piana and Carloni, 2000;Piana et al, 2001). These studies were performed either for the native enzyme or complexed with various inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of the First Steps of the Reaction Catalyzed by HIV-1 Protease

Trylska

Bała

Geller

et al. 2002

Biophysical Journal

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The mechanism of the first steps of the reaction catalyzed by HIV-1 protease was studied through molecular dynamics simulations. The potential energy surface in the active site was generated using the approximate valence bond method. The approximate valence bond (AVB) method was parameterized based on density functional calculations. The surrounding protein and explicit water environment was modeled with conventional, classical force field. The calculations were performed based on HIV-1 protease complexed with the MVT-101 inhibitor that was modified to a model substrate. The protonation state of the catalytic aspartates was determined theoretically. Possible reaction mechanisms involving the lytic water molecule are accounted for in this study. The modeled steps include the dissociation of the lytic water molecule and proton transfer onto Asp-125, the nucleophilic attack followed by a proton transfer onto peptide nitrogen. The simulations show that in the active site most preferable energetically are structures consisting of ionized or polarized molecular fragments that are not accounted for in conventional molecular dynamics. The mobility of the lytic water molecule, the dynamics of the hydrogen bond network, and the conformation of the aspartates in the active center were analyzed.

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“…These coordinates were also used in modeling studies of inhibitor binding to HIV‐2 PR,29 and to determine the X‐ray structures of several complexes with the recombinant enzyme 30. The structure was used for the molecular mechanics analysis of inhibitor binding to HIV‐1 PR,31, 32 and for a number of molecular dynamics simulation studies 33–35…”

Section: Crystal Structures Of Chemically Synthesized Hiv1‐prmentioning

confidence: 99%

The early years of retroviral protease crystal structures

Miller¹

2010

Biopolymers

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Soon after its discovery, the attempts to develop anti-AIDS therapeutics focused on the retroviral protease (PR) — an enzyme used by lentiviruses to process the precursor polypeptide into mature viral proteins. An urgent need for the three-dimensional structure of PR to guide rational drug design prompted efforts to produce milligram quantities of this enzyme. However, only minute amounts of PR were present in the HIV-1 and HIV-2 viruses, and initial attempts to express this protein in bacteria were not successful. This review describes X-ray crystallographic studies of the retroviral proteases carried out at NCI-Frederick in the late 1980s and early 1990s and puts into perspective the crucial role that the total protein chemical synthesis played in unraveling the structure, mechanism of action, and inhibition of HIV-1 PR. Notably, the first fully correct structure of HIV-1 PR and the first cocrystal structure of its complex with an inhibitor (a substrate-derived, reduced isostere hexapeptide MVT-101) were determined using chemically synthesized protein. Most importantly, these sets of coordinates were made freely available to the research community and were used worldwide to solve X-ray structures of HIV-1 PR complexes with an array of inhibitors and set in motion a variety of theoretical studies. Publication of the structure of chemically synthesized HIV-1 PR complexed with MVT-101 preceded only by six years the approval of the first PR inhibitor as an anti-AIDS drug.

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Analysis of the structure of HIV-1 protease complexed with a hexapeptide inhibitor. Part II: Molecular dynamic studies of the active site region

Cited by 15 publications

References 25 publications

Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations

Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations

Molecular Dynamics Simulations of the First Steps of the Reaction Catalyzed by HIV-1 Protease

The early years of retroviral protease crystal structures

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