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.
Although HIV-1 subtype B still dominates the epidemic AIDS in developed countries,an increasing number of people in developing countries are suffering from an epidemic of non-subtype B viruses.What is worse,the efficacy of the combinational use of antiretroviral drugs is gradually compromised by the rapid development of drug resistance.To gain an insight into drug resistance, 10-ns MD simulations were simultaneously conducted on the complexes of the TL-3 inhibitor with 4 different proteases(Bwt,Bmut, Fwt and Fmut),among which the complex of the Bwt protease with the TL-3 inhibitor was treated as the control group.Detailed analyses of MD data indicated that the drug resistance of Bmut against TL-3 mainly derived from loss of an important hydrogen bond and that of Fwt was caused by the decrease of hydrophobic interactions in S1/S1'pocket,while both of the two reasons mentioned above were the cause of the Fmut protease's resistance.These results are in good agreement with the previous experiments, revealing a possible mechanism of drug resistance for the aforementioned protease subtypes against the TL-3 inhibitor.Additionally,another indication was obtained that the mutations of M36I,V82A and L90M may induce structural transforms so as to alter the inhibitor's binding mode.
