Molecular Dynamics Analysis Of Allosteric Inhibitors System For HIV-1 Protease

Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family)that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in whichprogressive failure of the immune system allows life-threatening opportunistic infections andcancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid,pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virusparticles and virus within infected immune cells. The four major routes of transmission areunsafe sex, contaminated needles, breast milk, and transmission from an infected mother to herbaby at birth (perinatal transmission). Screening of blood products for HIV has largelyeliminated transmission through blood transfusions or infected blood products in the developedworld.HIV-1 protease (HIV PR) is a retroviral aspartyl protease (retropepsin) that is essential forthe life-cycle of HIV, the retrovirus that causes AIDS. HIV PR cleaves newly synthesizedpolyproteins at the appropriate places to create the mature protein components of an infectiousHIV virion. Without effective HIV PR, HIV virions remain uninfectious. Thus, mutation of HIVPR’s active site or inhibition of its activity disrupts HIV’s ability to replicate and infectadditional cells, making HIV PR inhibition the subject of much pharmaceutical research.Molecular dynamics (molecular dynamics, MD) is an important tool for study ofbiomolecules’structure and properties. For a molecular systems which is made up of a largenumber of interacted atoms. In molecular dynamics, the interaction between atoms expressed bypotential energy functions and the motion of individual atom in system governed by Newton’sequation. By solving a system dynamic equations，we get a piece of evolution trajectory in phasespace. Physical quantities, such as energy，density，of the system can be extracted usingstatistical mechanics method. Molecular dynamics can simulate the motion of complicatedmany-body biomolecules, just knowing the potential energy functions of the system. The resultsof molecular dynamics simulation can help us understanding the structure and function ofbiomolecules.Binding free energy calculation is very important to the mechanism between inhibitors and protein. Accurate prediction of binding free energy，can make us better understanding ofstructure and function relations of biological macromolecules，provides the basis for reasonableinhibitor design. Molecular mechanics / Poisson-Boltzman surface area (MM-PBSA) method iswidely used to calculation binding free energy which is based on the empirical equation. Thepositive and negative of binding free energy determines the direction of chemical reaction，andthe size of which determines the strength of the reaction trend.In this work, we performed 8 ns molecular dynamics simulation for allosteric inhibitorsystem and active site inhibitor system of HIV-1 protease. The binding free energy of twosystems was calculated with MM-PBSA method. The binding free energy of protease with it’sinhibitor in allosteric inhibitor system is -90.30 kcal/mol while in active site inhibitor systemwhich is -59.58 kcal/mol. Molecular fragment 4DX stuck at“exo”site of protease in allostericinhibitor system reduces the scope of activities of residues near the active site, has favorableeffect on binding with inhibitor. The allosteric inhibitor system is more rigid and stable thanactive site inhibitor system and the combination between inhibitor and protease is more firmly.