Exploring the reasons for decrease in binding affinity of HIV-2 against HIV-1 protease complex using interaction entropy under polarized force field

Yalong Cong, Yuchen Li, Kun Jin, Susu Zhong, John Zhang, Hao Li, Lili Duan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number380
JournalFrontiers in Chemistry
Volume6
Issue numberAUG
DOIs
StatePublished - Aug 1 2018

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Entropy
Free energy
HIV Protease
Atoms
Protonation
Linings
Water
Human immunodeficiency virus 1 p16 protease
3'-(1-butylphosphoryl)adenosine
Darunavir
amprenavir
Human immunodeficiency virus 2 p16 protease

Keywords

  • Binding free energy calculation
  • HIV protease
  • Interaction entropy
  • Molecular dynamics simulations
  • Polarized force field

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Exploring the reasons for decrease in binding affinity of HIV-2 against HIV-1 protease complex using interaction entropy under polarized force field. / Cong, Yalong; Li, Yuchen; Jin, Kun; Zhong, Susu; Zhang, John; Li, Hao; Duan, Lili.

In: Frontiers in Chemistry, Vol. 6, No. AUG, 380, 01.08.2018.

Research output: Contribution to journalArticle

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