The Theoretical Studies Involved Interactions Between HIV-1 Protease And Its Inhibitors

Acquired immunodeficiency syndrome, simply called AIDS, is mainly caused by human immunodeficiency virus I, i.e. HIV-1. AIDS is a kind of zoonosis disease with high death rate. It has been the fourth death reason in the world. The rapid prevalence of AIDS in the entire world dramatically threatens human's lives and health. The effective therapeutics of AIDS is a challengeable difficulty and the drug design for it is the hot field for theoretical researches currently and in the future.In the copy procedure of HIV-1 gene group, there are three kinds of key enzyme, i.e. HIV-1 reverse transcriptase (RT), protease (PR) and intergrase (IN). PR is a homodimer with C2 symmetry, and each polypeptide chain is composed of 99 amino acids. Its function in the life cycle of virus is producting HIV-1 into matural virus particles which can infect host cells, thus PR is an important target for the development of AIDS'drugs.Protease inhibitors (PIs) are some compounds which can inhibit PR's activity. Its mechanism is simulating the binding of peptide and PR to inhibit PR's activity and to prevent the copy of HIV-1. Thus PIs are important anti-AIDS drugs. Theoretical study for the interaction of PR and PIs is performed in this paper, which is essential for the design and development of anti-AIDS drugs.In the last 20 years, lots of researches for AIDS therapeutics in theory and experiment have been done and made great progress. But there are many difficulties in determining the structures of PR and its PIs in experiment, theoretical study is very important for this field. On the other hand, the increasing of the data-dealing ability of computer and the development of theoretical simulation methods give strong technological and methodical support to the theoretical study. Currently, molecular dynamics (MD) and free energy calculation have become very important tools to study the structures, dynamics and thermodynamic properties for bimolecules. MD simulation can give the motional detail at the atomic level and the detail information of position's draft and construction change. Accurate free energy prediction can make us understand the relationship of bimolecular structure and function, and give accordance to rational drug design. Recently, molecular mechanics/Poisson-Boltzman surface area (MM-PBSA) method is an extensive applicable free energy method based on empirical equation.In this paper, we use MD simulation and MM-PBSA method to investigate the interaction of PR and its PIs, mainly composed by three parts as following.1,The study of the interaction mechanisms of PIs BEC and BEG with PRTwo PIs BEC and BEG which were approved by the U.S. Food and Drug Administration recently were selected to investigate the PR-PI interactions with MD simulation and MM-PBSA method. The RMSD values of PR Cαatoms relative to the initial structure through the MD simulations were calculated and analyzed, and the analyses of superimposition of the crystal structures with the average structures of two complexes during the last 1ns of the MD trajectories via backbone atoms were carried out. MM-PBSA method involving the single trajectory protocol was performed to calculate the binding free energies, and the interaction spectra were calculated by the free energy decomposition. The results suggest that the stabilities of the dynamic equilibriums for two complexes are reliable and Van der Waals energies mostly drive the bindings of this class of inhibitors to the PR. For the case of two complexes, the favorable interactions come from Gly27, Ala28/Ala28′, Gly49, Ile50/Ile50′and Ile84/Ile84′. The favorable interactions mainly are produced by the three types of interactions: the hydrogen bond interactions, the C-H…πinteractions and the C-H…H-C interactions. These interactions of BEC and BEG with the PR play important roles in the binding of BEC and BEG to the PR. The improvement and optimization of these interactions may benefit the rational design of potent inhibitors combating AIDS.2,The study of the role of protonation states in PR-Indinavir complexIndinavir (IDV) is a PI which is used to combat PR early. The interaction of PI and IDV is effected by the protonation state of Asp25/Asp25′, but the crystal structure determined by the experiment can't give the information about the protonation directly, so the protonation state of Asp25/Asp25′in PR-IDV complex is important for us to study the binding mechanism and the drug resistance induced by the mutation in theory. 5 ns molecular dynamic simulations have been performed for six possible protonation states, and the influences on dynamics behavior and structure caused by different protonation states were analyzed, and relative binding free energies were calculated by using the MM-PBSA method. The results show that the protonation state of OD2 from Asp25 in chain A is the most possible. The hydrogen bonds between the water molecule that plays a medium role and the PR-IDV complex were also analyzed, and the results show that the different states have not obvious influences on the medium role, which is different from our previous result on PR-BEA369 complex. It was expected that this study could provide a significative help for the high affinity inhibitor design and the mutation induced drug resistance research.3,The study of functional role of water molecules buried within binding pocket of PR with PI TMC114Water molecules play an important role in the stability, dynamics, function and recognition of bimolecules. Many studies showed that water molecules not only act as a bridge between PIs and PR, but also stabilize the structure of PR. TMC114 is a next-generation nonpeptidic PI that is extremely potent to inhibit the activation of PR. Five water molecules, i.e. Wat301,Wat2,Wat5,Wat89 and Wat211, have been observed within the binding packet of PR with TMC11. 3 ns MD simulations have been successfully performed for PR-TMC114 complexes, one with five water molecules in the binding packet, and another without. The RMSD values of PR's Cαatoms relative to the initial structure through the MD simulations were calculated, and the analyses of superimposition of the crystal structure with the average structure during the last 1ns of the MD trajectories via backbone atoms were carried out. The hydrogen bond used to describe the binding specificity was analyzed, too. The results indicate that the water molecules can maintain the stability of the structure of complex PR-TMC114, and Wat301, Wat2 and Wat5 are conserved during MD simulation. Wat301 has an ability to maintain the stability of the flaps and TMC114. The restrictions produced by the hydrogen bonds involved 5 water molecules make the residues and TMC114 stay in their original positions during simulation. We expect that this study can provide a significant insight into the function of water molecules in PR-PI complex, and also give some favorable help for the design of potent PIs.