Phospholamban is an important protein with responsibility for regulating the activity of the sarcoplasmic reticulum Ca2+ pump through reversible phosphorylation.And its three-dimensional structure in living cell has been a focus of attention.In the current case, we summarized the investigations on phospholamban structure, and on this base, employed long time-scale molecular dy-namics simulations to study its structure systematically.The first 22 residues from one chain of phospholamban in bellflower structure determined by NMR experiments, together with its phosphorylation at position 16 and mutation at position 9 were picked up as three different systems.By molecular dynamics simulations of 10 ns in the explicit solution surroundings, it was found that the 3–15 residues of the original structure retained their helix structures, while the phosphorylation and mutation had less probability to form helix structures.These structural changes might result in inhibition decrease to the sarcoplasmic reticulum Ca2+ pump, which is in accordance with previous experimental results.
Drug-metabolizing enzymes,also known as cytochrome P450s,are a superfamily of hemoglobin responsible for metabolizing more than 90% clinical drugs.Cytochrome P450 2D6(CYP2D6) is a significant member of cytochrome P450s for the reason of metabolizing about 20% clinical drugs.In this paper,molecular docking and molecular dynamic simulations are used to investi-gate the active site of CYP2D6,roles of essential amino acids within the active site and time-dependent protein energy changes.The results suggest that amino acids Glu216,Asp301,Ser304 and Ala305 in the active site are likely to form hydrogen bonding interactions with substrates;the benzene ring of Phe120 and aromatic ring in the substrates form Π-Π interactions.In addition,molecular dynamics simulations prove that the catalytic conformation of CYP2D6 without ligands can be obtained by their own atomic fluctuations.The impact of ligands on protein system energy and large conformational shift is not very large.Cytochrome P450s is known for their genetic polymorphisms,which will result in severe adverse drug reactions.Ideally,we hope to use mo-lecular modeling to investigate the differences between the substrates of wild-type and mutants while they are bonded with drugs,and predict the drug metabolizing ability of mutants.Reduce the possibility for people taking drugs that they can not metabolize,therefore reduce the rate of adverse drug reactions,and eventually establish a platform of personalized drugs to largely benefit human health.
The metabolic network has become a hot topic in the area of system biology and flux-based analysis plays a very important role in understanding the characteristics of organism metabolic networks. We review mainly the static methods for analyzing metabolic networks such as flux balance analysis (FBA), minimization of metabolic adjustment (MOMA), regulatory on / off minimization (ROOM), and dynamic flux balance analysis with linear quadratic regulator (DFBA-LQR). Then several kinds of commonly used software for flux analysis are introduced briefly and compared with each other. Finally, we highlight the applications of metabolic network flux analysis, especially its usage combined with other biological characteristics and its usage for drug design. The idea of combining the analysis of metabolic networks and other biochemical data has been gradually promoted and used in several aspects such as the combination of metabolic flux and the regulation of gene expression, the influence of protein evolution caused by metabolic flux, the relationship between metabolic flux and the topological characteristics, the optimization of metabolic engineering. More comprehensive and accurate properties of metabolic networks will be obtained by integrating metabolic flux analysis, network topological characteristics and dynamic modeling.
