Molecular Dynamics Simulation Of Protein Structure And Dynamics

Protein is the basic functional unit for most physiological activities. The proteinmobility which also act as flexibility is very important for their functions. Proteinsaccomplish their physiological functions with remarkably organized dynamictransitions among a hierarchical network of conformational substates. Moleculardynamics simulation is a widely used method for protein conformational substatesinvestigation. MD method could show characteristics of protein kinetics andthermodynamics, especially how protein moving on atomic level. We all know,proteins perform their functions through interaction, which mostly in the waterenvironment, accompanied with conformation transition. Therefore, it is important tofigure out how water molecules affect proteins’ conformation, how conformationchanged during protein binding. Conformation space analysis and conformationalentropy estimation should make these more clear.The main contents of this dissertation are as below:1) Water play an indispensable role in shaping dynamic behaviour of proteinsthrough molecular interactions that modify protein potential energy surface. Wesystematically analysed protein self energies and protein-water interaction energiesobtained from extensive molecular dynamics simulation trajectories of barstar. Wefound that water molecules effectively roughen potential energy surface of proteins inthe majority part of observed conformational space and smooth in the remaining part.These findings support a scenario wherein water on average slave proteinconformational dynamics but facilitate a fraction of transitions among differentconformational substates, and reconcile the controversy on the facilitating and slavingroles of water molecules in protein conformational dynamics.2）The most majority proteins perform their specially biological activity throughinteraction with others. There are two important long-stand assumptions about protein-ligand binding which are “induced-fit” and “conformational selection”. Wedemonstrate these questions from the aspects of conformational substates. Weperformed molecular dynamics simulation in a microsecond timescale for three setsof proteins and study the conformational substates change before and after proteinbinding, as well as the transform frequency of dihedral angles and conformations.We found that the two assumptions work at the same time, for most proteins“induced-fit” play a dominate role, while for some others “conformational selection”are in dominate. We found that the loop is a key area for protein interaction, we alsogive a quantitative description for the flexibility of protein structure from the aspectsof protein conformational substates.3）The estimation of entropy is a challenging problem for macromolecules suchas protein. Despite great progresses that have been made, the global samplingremains to be a challenge for computational analysis of relevant processes. Here wepropose an entropy estimation method which based on physical partition ofconfigurational space and can be readily combined with currently availablemethodologies. Tests with two globular proteins suggest that accurateconfigurational entropy estimation can be achieved simply by considering theentropically most important subspace, thus convert an exhaustive sampling probleminto a local sampling problem. We also performed some calculation for protein, andwe found entropy loss during protein-protein binding, together with the results weget from protein-protein conformation analysis, it proved that the protein-proteininteraction is a process driven by entropy.