Substrate recognition and motion mode analyses of PFV integrase in complex with viral DNA via coarse-grained models.

Jianping Hu,Ming Liu,Dianyong Tang,Shan Chang

doi:10.1371/journal.pone.0054929

Jianping Hu, Ming Liu + Show 2 more

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https://doi.org/10.1371/journal.pone.0054929

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Abstract

HIV-1 integrase (IN) is an important target in the development of drugs against the AIDS virus. Drug design based on the structure of IN was markedly hampered due to the lack of three-dimensional structure information of HIV-1 IN-viral DNA complex. The prototype foamy virus (PFV) IN has a highly functional and structural homology with HIV-1 IN. Recently, the X-ray crystal complex structure of PFV IN with its cognate viral DNA has been obtained. In this study, both Gaussian network model (GNM) and anisotropy network model (ANM) have been applied to comparatively investigate the motion modes of PFV DNA-free and DNA-bound IN. The results show that the motion mode of PFV IN has only a slight change after binding with DNA. The motion of this enzyme is in favor of association with DNA, and the binding ability is determined by its intrinsic structural topology. Molecular docking experiments were performed to gain the binding modes of a series of diketo acid (DKA) inhibitors with PFV IN obtained from ANM, from which the dependability of PFV IN-DNA used in the drug screen for strand transfer (ST) inhibitors was confirmed. It is also found that the functional groups of keto-enol, bis-diketo, tetrazole and azido play a key role in aiding the recognition of viral DNA, and thus finally increase the inhibition capability for the corresponding DKA inhibitor. Our study provides some theoretical information and helps to design anti-AIDS drug based on the structure of IN.

Highlights

Integrase (IN) is one of the three key enzymes involved in the life cycle of the HIV-1 virus
The motion modes of prototype foamy virus (PFV) IN and IN-DNA systems are investigated with Gaussian network model (GNM) and anisotropic network model (ANM) methods
The B-factors calculated via GNM agree well with the experimental data, and the binding site of PFV IN with DNA is correctly found, which confirm the reliability of coarse-grained models

Summary

Introduction

Integrase (IN) is one of the three key enzymes involved in the life cycle of the HIV-1 virus. The full-length HIV-1 IN comprises 288 residues, which can be divided into three domains, i.e. the Nterminal domain (NTD, residues 1,50), the catalytic core domain (CCD, residues 51,211) and the C-terminal domain (CTD, residues 212,288). NTD contains a conserved ‘‘HHCC’’ motif binding with a Zn2+ ion and can promote enzymatic multimerization [1,2]. CCD is composed of six a-helixes and five bsheets, and contains an absolutely conserved D-D-35-E motif (i.e. Asp, Asp116, Glu152) chelated by two Mg2+ ions. CTD has relative poor conservations and is found to strongly and non- bind with different DNA sequences [6,7]. The first step is termed as 39 end processing [10], in which two nucleotides are removed from 39-end of each strand of viral DNA to produce a functional base end (i.e. Cytosine-adenine, CA). The second step named as DNA strand transfer (ST) occurs in the nucleus [11], where the CA end of viral DNA is covalently joined to the host DNA

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