Molecular Dynamics Simulation Study On The Transport Mechanisms Of Secondary Active Transporters

Secondary active transporters use the energy of the transmembrane electrochemical potential provided by "downhill" of one solute to lead to "uphill" translocation of another solute molecule across plasma membrane; they are ubiquitously distributed in every cell. On one hand, they are responsible for transporting the molecules across membranes, including ions, sugars, amino acids, peptides and nucleobases etc. On the other hand, they play an important role in signal transduction, mechanosensing, energy conversion and multidrug resistance processes. Over the past years, the structures of secondary active transporters obtained through X-ray and EM crystallography techniques has greatly assisted our understanding of the transport mechanism of them. The transport process is a dynamic process, so the static crystal structure cannot provide dynamic details about the transport mechanism, even if the structures are in high resolution status. With the rapid development of computational technology and information science technology, molecular modeling methods have been widely applied in the study of dynamics and mechanism of bio-molecule. In the present thesis, classical molecular dynamics (CMD) simulation and steered molecular dynamics (SMD) simulation have been applied to study the transport mechanism of two secondary active transporters, including nitrate/nitrite exchanger and multidrug/H+transporter. The present thesis mainly consists of three chapters, which is summarized as follows:In Chapter1, we mainly introduced the general classification and common structural features of the secondary active transporters. We also gave a brief introduction about the fundamental principles of molecular dynamics simulation. At the same time, we also summarized the applications of molecular dynamics simulation to the secondary active transporter study in the past few years.In Chapter2, CMD simulation approach was performed to study the transport mechanism of the nitrate/nitrite exchanger (NarK), and SMD simulation approach was applied to explore the pathway for nitrite unbinding. The results of this study can provide some theoretical guidance for understanding the transport mechanism and unbinding pathway of NarK.In Chapter3, we applied CMD simulation to study the conformational change and unbinding pathway of multidrug/H+transporter (pfMATE) induced by protonation and deprotonation of ASP41. Ours results can provide useful information to further interpret the couple mechanism between the substrate and proton, and also help us gain a deep understanding of the molecular mechanism of multidrug resistance.