Hybrid QM/MM Study On Protein-ligand Binding

Dynamic simulation methods are widely used to obtain information on the time evolution of conformations of proteins and other biological macromolecules and also kinetic and thermodynamic information. They can be utilized to quantify the properties of a system at a precision and on a time scale that is otherwise inaccessible. Thus, molecular dynamics simulations, along with a range of complementary computational appoaches, have become valuable tools for investigating the basis of protein structure and function.A QM/MM method treats a localized region, e.g., the active site and its neighbors in an enzyme, with QM methods and includes the influence of the surroundings(e.g., the protein enviroment,) at the MM level. 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, so it is suitable for the simulaton of proteins. Now, only some lower QM theroy can be adopted by QM/MM method,such as semiempirical method, density functional theory(DFT). AM1 and PM3 are among the most famous ones of semiempirical methods.The purpose of a MD simulation is often to derive kinetic and thermodynamic data about the model system. One very important thermodynamic quantity is free energy, a measure of the stability of a system. In particular, free energy of binding is a measure of the stability of a complex, a measure that is probably fundamental to all studies of biomolecular binding processes. There are many approaches available for estimating binding free energy, such as free energy perturbation(FEP) method, thermodynamic integration(TI) method , molecular mechanics/Poisson Boltzmann surface area(MM/PBSA) method.Human Immunodeficiency Virus(HIV) is the causative agent of the pandemic disease Acquired Immune Deficiency Syndrome(AIDS). HIV-1 protease is essential for HIV-1 replication. Twenty years of research by countless scientists around the world had led to the discovery and exploitation of several targets in the replication cycle of HIV-1. One particularly successful target has been the inhibiton of HIV-1 protease. Nine protease inhibitor have been approved by the FDA. Recently, Jenny K. Ekegren et al. studied a new class of protease inhibitors, among which are 2AH and 4AH.An extensive set of X-ray crystal structures of HIV-1 protease-inhibitor complexes revealed that the active site region of protease is covered by two glycine-richβhairpins,which can ineract with inhibitors through a bridging water W301. Bridging water W301 was observed in both 2AH complex and 4AH complex.In this work, we performed 1ns molecular dynamic simulations of hybrid quantum mechanics/molecular mechanics (QM/MM) for two compounds that were formed by the binding of HIV-1 protease and inhibitors 2AH and 4AH in water solution. The binding free energy of interfacial water molecule W301 and the compounds of HIV-1 protease and inhibitors 2AH and 4AH by MM-GBSA were -24.93kJ/mol and -20.29 kJ/mol. It demonstrated that W301 played an important role in the binding of HIV-1 protease and inhibitor, so it was not neglectable. In addition, we performed hydrogen bonds analysis for interfacial water molecule W301.This dissertation is composed of five chapters. In chapter 1, we expound the importance of exploring the role of interfacial water molecule W301 in HIV-1 protease /inhibitor complex, and review the work of associated research group, briefly introducing their research methods. Chapter 2, theory and method, contains the basic knowledge of molecular mechanics, molecular dynamics simulation, QM/MM method and free energy calculation. Understanding of HIV-1 protease, inhibitors 2AH and 4AH, and interfacial water molecules could be gained from chapter 3. Our workflow detail is in chapter 4. Results and conclusions are put in chapter 5.