Molecular Dynamics Simulation For Two Kinds Of Estrogen Receptors Binding With Inhibitors

Molecular dynamics (molecular dynamics,MD) is an important tool for study of biomolecules'structure and properties. For a molecular systems which is made up of a large number of interacted atoms, In molecular dynamics, the interaction between atoms expressed by potential energy functions, the motion of individual atom in system governed by Newton's equation. By solving a system dynamic equations,we get a piece of evolution trajectory in phase space. Physical quantity, such as energy,density,of the system can be extracted using statistical mechanics method. Molecular dynamics can simulate the motion of complicated many-body biomolecules, just knowing the potential energy functions of the system. The results of molecular dynamics simulation can help us understanding the structure and function of biomolecules.QM/MM method takes advantage of the accuracy of quantum mechanics and efficiency in computation of molecular mechanics. Use quantum mechanics to deal with the part which involves important, chemical bond change in the system. For secondary system, not directly involve chemical bonds change, use molecular mechanics method to describe. Comparing to complete MM method, QM/MM method describes the changes in the electronic structure of a system better. And this method has lower computational cost than complete QM method. The semi-empirical method and density functional theory only can be adopted by QM/MM method. Through comparative molecular dynamic calculation results we can discover the calculate results of QM/MM method are more accurate.Binding free energy calculation is very important to the mechanism between inhibitors and protein. Accurate predict of binding free energy,can make us to better understand the structure and function relations of biological macromolecules,provides the basis for reasonable inhibitor design. Molecular mechanics / Poisson-Boltzman surface area,(MM-PBSA) method is widely used to calculation binding free energy which is based on the empirical equation. The positive and negative of binding free energy determines the direction of chemical reaction,its size determines the strength of the reaction trend.Estrogen ( Estrogen Response ) plays a key role in the female reproductive system development and physiological processes,and also has an important role in controlling blood calcium levels and maintain bone density. Estrogen and estrogen receptor (estrogen receptor,ER) play a role through the interaction between them. There have two kinds of estrogen receptor ERαand ERβhave been discovered. An extensive set of X-ray crystal structures of two system revealed that they are very similar in their active areas, only in the binding pocket near there are two different residues ,Leu384 and Met421 in ERαrespectively corresponding Met336 and Ile373 in ERβ,these small differences lead to ERαand ERβplay different role with inhibition. Study action mechanisms of two systems with inhibitors to design high selectivity inhibitors have important meaning.In this work, we performed 12ns molecular dynamic simulations for two systems in water solution, discussed the conformational changes of two system. The binding free energy of two estrogen response and inhibitors 244 by MM-PBSA were -30.11 kJ/mol and -37.87 kJ/mol, it demonstrated that ERβand inhibitors are more easily combine, forming the structure more stable. Electrostatic repulsion between Met421 side chain in of ERαand inhibitor changes the residues conformation of the active pocket. This causes bigger binding cavity and further decreases the binding of ERαand the inhibitor. We performed 1ns QM/MM simulations for the two systems in water solution. Through comparative molecular dynamic calculation results we discover that the calculate results of QM/MM method are more accurate.This thesis is organized as follows: Chapter 1 briefly presents the structure,function of estrogen receptor (ER),and the development of estrogen receptor inhibitors; Chapter 2 describes the theory and methods used in this work, include molecular mechanics,hybrid quantum mechanics molecular dynamics simulations and free energy calculation; The procedure of molecular dynamics simulations for ERαand ERβwith inhibitor described in Chapter 3; Chapter 4 describes the conformational changes of ERαand ERβsystem during simulation, presents the calculations results of free energy; Our calculated results are also compared with results of QM/MM methods calculations in Chapter 5.