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.
Highlights
Acquired immunodeficiency syndrome (AIDS) has been a major global health challenge due to its serious threat to human life.According to data of The Joint United Nations Programme on HIV/AIDS (UNAIDS), around 36.7 million people within the worldwide are infected with HIV in recent years
Our work focuses on the investigation for the differences of binding patterns between two PRs and inhibitors, besides discussing the origin of the decrease in affinity of two inhibitors against HIV-2 protease compared with human immunodeficiency virus type-1 (HIV-1) protease by molecular dynamics (MD) simulation and the binding free energy calculation
In order to evaluate the stability of the system during MD simulations, the root mean square deviation (RMSD) of the protein backbone atoms relative to the corresponding crystal structure is calculated
Summary
Acquired immunodeficiency syndrome (AIDS) has been a major global health challenge due to its serious threat to human life.According to data of The Joint United Nations Programme on HIV/AIDS (UNAIDS), around 36.7 million people within the worldwide are infected with HIV in recent years. As the most common type, HIV-1 which is divided into four groups (M, N, O, and P) and several subtypes (Tie et al, 2012), is observed around the global Another type, HIV-2, is firstly identified in West Africa (Guyader et al, 1987; Menéndez-Arias and Tözsér, 2008; Peterson et al, 2011), but it is found which is gradually spreading to other parts of the world (Soriano et al, 2000; Barin et al, 2007; Kovalevsky et al, 2008). HIV-1 protease (PR1) (Navia et al, 1989) is extremely effective as a drug target for AIDS treatment (Debouck, 1992) It plays an essential role in the life cycle of HIV by cleaving the Gag and Gag-pol non-functional polypeptides into mature and infectious HIV viral particles (Wlodawer and Vondrasek, 1998; Louis et al, 2000). The design of new inhibitor specially targeting PR2 is urgent for those treatment of patients infected by HIV-2
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