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Interaction of HIV-1 aspartic protease with its inhibitor, by molecular dynamics and ab initio fragment molecular orbital method.

Koyano K, Nakano T - J Synchrotron Radiat (2008)

Bottom Line: The interaction energy of the inhibitor at the active sites of aspartic acid is as great as 50 kcal mol(-1), coinciding with a tetrahedral transition state.The difference in symmetry of the inhibitor was not evident.Binding free energy corresponds to the experimental value of the binding constant, while molecular orbital energy does not always, which is considered to be an entropy effect.

View Article: PubMed Central - HTML - PubMed

Affiliation: Advance Soft Co. Ltd, Center for Collaborative Research, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan. kkoyano@n02.itscom.net

ABSTRACT
For the three complex crystal structures of HIV-1 aspartic protease (an enzyme of AIDS) with its inhibitor in the Protein Data Bank, molecular dynamics of the generalized Born surface area and the ab initio fragment molecular orbital of an ABINIT-MP calculation was performed to obtain the binding free energy, the molecular orbital energy, the interaction energy of residues with an inhibitor and the charge transfer at the active site. The inhibitors are five symmetric cyclic ureas, of which three were modelled, and an asymmetric dipeptide. The interaction energy of the inhibitor at the active sites of aspartic acid is as great as 50 kcal mol(-1), coinciding with a tetrahedral transition state. For the inhibitor with a higher affinity, charge was transferred to the inhibitor from the active site. The difference in symmetry of the inhibitor was not evident. Binding free energy corresponds to the experimental value of the binding constant, while molecular orbital energy does not always, which is considered to be an entropy effect.

Show MeSH
Interacton of HIV-1 PR residues and inhibitors XK1–BEH. Energy in kcal mol−1; numbering of residues is through the dimer; each has 99 residues.
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fig5: Interacton of HIV-1 PR residues and inhibitors XK1–BEH. Energy in kcal mol−1; numbering of residues is through the dimer; each has 99 residues.

Mentions: As stated in the Introduction, in HIV-1 PR, Asp25 and Asp124 at the active sites hydrolyze a peptide bond of the substrate catalytically via not a triangular but a tetrahedral transition state bearing a negative charge like other PRs (Ser PR for example; Branden & Tooz, 1999 ▶), as shown in Fig. 4 ▶ (Doi et al., 2004 ▶). ABINIT-MP is able to calculate not only the total binding energy but also the interaction between residues of the receptor and the inhibitor, and the charge transfer from the receptor to the inhibitor at the active site, , where the complex consists of a receptor and an inhibitor (Nakano & Kato, 2004 ▶). The electric charge was calculated using Mulliken’s method. The interaction energies of the inhibitors and the protease are shown in Fig. 5 ▶. The interactions at the active sites, Asp25 and Asp124, are as great as 50 kcal mol−1, corresponding to the tetrahedral transition state. The interactions are not necessarily balanced at both sites in symmetrical cyclic urea inhibitors (XK series and AH1), but conversely the lower the binding constant, the more balanced the interaction. Hydrogen bonds are formed between the inhibitors, AH1 and BEH, and the active sites, Asp25 and Asp124, as shown in Fig. 6 ▶, corresponding to the transition state. In the symmetric cyclic urea inhibitor AH1, the two hydrogen-bond lengths between the hydroxy group of AH1 and sites Asp25 and Asp124 are almost equal (1.961 and 1.870 Å, respectively), while in the asymmetric dipeptide BEH, the length difference is greater (1.928 and 2.559 Å). The charge transferred from the receptor to the inhibitor, , at the active sites of the two complex crystals is shown in Table 2 ▶. At the active site Asp25, the charge transfer from receptor to inhibitor of high-affinity BEH is larger than that of low-affinity AH1, while at the other site, Asp124, the direction of the charge transfer is reversed and the value is low.


Interaction of HIV-1 aspartic protease with its inhibitor, by molecular dynamics and ab initio fragment molecular orbital method.

Koyano K, Nakano T - J Synchrotron Radiat (2008)

Interacton of HIV-1 PR residues and inhibitors XK1–BEH. Energy in kcal mol−1; numbering of residues is through the dimer; each has 99 residues.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2394819&req=5

fig5: Interacton of HIV-1 PR residues and inhibitors XK1–BEH. Energy in kcal mol−1; numbering of residues is through the dimer; each has 99 residues.
Mentions: As stated in the Introduction, in HIV-1 PR, Asp25 and Asp124 at the active sites hydrolyze a peptide bond of the substrate catalytically via not a triangular but a tetrahedral transition state bearing a negative charge like other PRs (Ser PR for example; Branden & Tooz, 1999 ▶), as shown in Fig. 4 ▶ (Doi et al., 2004 ▶). ABINIT-MP is able to calculate not only the total binding energy but also the interaction between residues of the receptor and the inhibitor, and the charge transfer from the receptor to the inhibitor at the active site, , where the complex consists of a receptor and an inhibitor (Nakano & Kato, 2004 ▶). The electric charge was calculated using Mulliken’s method. The interaction energies of the inhibitors and the protease are shown in Fig. 5 ▶. The interactions at the active sites, Asp25 and Asp124, are as great as 50 kcal mol−1, corresponding to the tetrahedral transition state. The interactions are not necessarily balanced at both sites in symmetrical cyclic urea inhibitors (XK series and AH1), but conversely the lower the binding constant, the more balanced the interaction. Hydrogen bonds are formed between the inhibitors, AH1 and BEH, and the active sites, Asp25 and Asp124, as shown in Fig. 6 ▶, corresponding to the transition state. In the symmetric cyclic urea inhibitor AH1, the two hydrogen-bond lengths between the hydroxy group of AH1 and sites Asp25 and Asp124 are almost equal (1.961 and 1.870 Å, respectively), while in the asymmetric dipeptide BEH, the length difference is greater (1.928 and 2.559 Å). The charge transferred from the receptor to the inhibitor, , at the active sites of the two complex crystals is shown in Table 2 ▶. At the active site Asp25, the charge transfer from receptor to inhibitor of high-affinity BEH is larger than that of low-affinity AH1, while at the other site, Asp124, the direction of the charge transfer is reversed and the value is low.

Bottom Line: The interaction energy of the inhibitor at the active sites of aspartic acid is as great as 50 kcal mol(-1), coinciding with a tetrahedral transition state.The difference in symmetry of the inhibitor was not evident.Binding free energy corresponds to the experimental value of the binding constant, while molecular orbital energy does not always, which is considered to be an entropy effect.

View Article: PubMed Central - HTML - PubMed

Affiliation: Advance Soft Co. Ltd, Center for Collaborative Research, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan. kkoyano@n02.itscom.net

ABSTRACT
For the three complex crystal structures of HIV-1 aspartic protease (an enzyme of AIDS) with its inhibitor in the Protein Data Bank, molecular dynamics of the generalized Born surface area and the ab initio fragment molecular orbital of an ABINIT-MP calculation was performed to obtain the binding free energy, the molecular orbital energy, the interaction energy of residues with an inhibitor and the charge transfer at the active site. The inhibitors are five symmetric cyclic ureas, of which three were modelled, and an asymmetric dipeptide. The interaction energy of the inhibitor at the active sites of aspartic acid is as great as 50 kcal mol(-1), coinciding with a tetrahedral transition state. For the inhibitor with a higher affinity, charge was transferred to the inhibitor from the active site. The difference in symmetry of the inhibitor was not evident. Binding free energy corresponds to the experimental value of the binding constant, while molecular orbital energy does not always, which is considered to be an entropy effect.

Show MeSH