TY - JOUR
T1 - Exploring the reasons for decrease in binding affinity of HIV-2 against HIV-1 protease complex using interaction entropy under polarized force field
AU - Cong, Yalong
AU - Li, Yuchen
AU - Jin, Kun
AU - Zhong, Susu
AU - Zhang, John Z.H.
AU - Li, Hao
AU - Duan, Lili
N1 - Funding Information:
This work was supported by National Key R&D Program of China (Grant no. 2016YFA0501700), National Natural Science Foundation of China (Grant nos. 11774207, 11574184, 21433004, 91753103), the Natural Science Foundation of Shandong Province (ZR2016JL003), Primary Research & Development Plan of Shandong Province (No. 2017GSF18108), Innovation Program of Shanghai Municipal Education Commission (201701070005E00020), and NYU Global Seed Grant. We thank the Supercomputer Center of East China Normal University for providing us computer time. This work was supported by National Key R&D Program of China (Grant no. 2016YFA0501700), National Natural Science Foundation of China (Grant nos. 11774207, 11574184, 21433004, 91753103), the Natural Science Foundation of Shandong Province (ZR2016JL003), Primary Research & Development Plan of Shandong Province (No. 2017GSF18108), Innovation Program of Shanghai Municipal Education Commission (201701070005E00020), and NYU Global Seed Grant. We thank the Supercomputer Center of East China Normal University for providing us computer time.
Publisher Copyright:
© 2018 Cong, Li, Jin, Zhong, Zhang, Li and Duan.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - In this study, the differences of binding patterns between two type HIV (HIV-1 and HIV-2) protease and two inhibitors (darunavir and amprenavir) are analyzed and compared using the newly developed interaction entropy (IE) method for the entropy change calculation combined with the polarized force field. The functional role of protonation states in the two HIV-2 complexes is investigated and our study finds that the protonated OD1 atom of Asp25' in B chain is the optimal choice. Those calculated binding free energies obtained from the polarized force field combined with IE method are significantly consistent with the experimental observed. The bridging water W301 is favorable to the binding of HIV-1 complexes; however, it is unfavorable to the HIV-2 complexes in current study. The volume of pocket, B-factor of Cα atoms and the distance of flap tip in HIV-2 complexes are smaller than that of HIV-1 consistently. These changes may cause localized rearrangement of residues lining their surface and finally result in the different binding mode for the two types HIV. Predicated hot-spot residues (Ala28/Ala28', Ile50/Ile50', and Ile84/Ile84') are nearly same in the four systems. However, the contribution to the free energy of Asp30 residue is more favorable in HIV-1 system than in HIV-2 system. Current study, to some extent, reveals the origin for the decrease in binding affinity of inhibitors against HIV-2 compared with HIV-1 and will provides theoretical guidance for future design of potent dual inhibitors targeting two type HIV protease.
AB - In this study, the differences of binding patterns between two type HIV (HIV-1 and HIV-2) protease and two inhibitors (darunavir and amprenavir) are analyzed and compared using the newly developed interaction entropy (IE) method for the entropy change calculation combined with the polarized force field. The functional role of protonation states in the two HIV-2 complexes is investigated and our study finds that the protonated OD1 atom of Asp25' in B chain is the optimal choice. Those calculated binding free energies obtained from the polarized force field combined with IE method are significantly consistent with the experimental observed. The bridging water W301 is favorable to the binding of HIV-1 complexes; however, it is unfavorable to the HIV-2 complexes in current study. The volume of pocket, B-factor of Cα atoms and the distance of flap tip in HIV-2 complexes are smaller than that of HIV-1 consistently. These changes may cause localized rearrangement of residues lining their surface and finally result in the different binding mode for the two types HIV. Predicated hot-spot residues (Ala28/Ala28', Ile50/Ile50', and Ile84/Ile84') are nearly same in the four systems. However, the contribution to the free energy of Asp30 residue is more favorable in HIV-1 system than in HIV-2 system. Current study, to some extent, reveals the origin for the decrease in binding affinity of inhibitors against HIV-2 compared with HIV-1 and will provides theoretical guidance for future design of potent dual inhibitors targeting two type HIV protease.
KW - Binding free energy calculation
KW - HIV protease
KW - Interaction entropy
KW - Molecular dynamics simulations
KW - Polarized force field
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U2 - 10.3389/fchem.2018.00380
DO - 10.3389/fchem.2018.00380
M3 - Article
AN - SCOPUS:85054673717
SN - 2296-2646
VL - 6
JO - Frontiers in Chemistry
JF - Frontiers in Chemistry
IS - AUG
M1 - 380
ER -