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Ensemble Molecular Dynamics of a Protein-Ligand Complex: Residual Inhibitor Entropy Enhances Drug Potency in Butyrylcholinesterase. 蛋白质-配体复合物的整体分子动力学:残余抑制剂熵增强了丁基胆碱酯酶的药物效力。

Bioenergetics : open access Pub Date : 2017-01-01 Epub Date: 2017-01-08 DOI: 10.4172/2167-7662.1000145

Eric J Sorin, Walter Alvarado, Samantha Cao, Amethyst Radcliffe, Phuc La, Yi An

{"title":"Ensemble Molecular Dynamics of a Protein-Ligand Complex: Residual Inhibitor Entropy Enhances Drug Potency in Butyrylcholinesterase.","authors":"Eric J Sorin, Walter Alvarado, Samantha Cao, Amethyst Radcliffe, Phuc La, Yi An","doi":"10.4172/2167-7662.1000145","DOIUrl":"https://doi.org/10.4172/2167-7662.1000145","url":null,"abstract":"Butyrylcholinesterase is a key enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine and shows an increased activity in patients suffering from Alzheimer's disease (AD), making this enzyme a primary target in treating AD. Central to this problem, and to similar scenarios involving biomolecular recognition, is our understanding of the nature of the protein-ligand complex. The butyrylcholinesterase enzyme was studied via all-atom, explicit solvent, ensemble molecular dynamics simulations sans inhibitor and in the presence of three dialkyl phenyl phosphate inhibitors of known potency to a cumulative sampling of over 40 μs. Following the relaxation of these ensembles to conformational equilibria, binding modes for each inhibitor were identified. While classical models, which assume significant reduction in protein and ligand conformational entropies, continue to be favored in contemporary studies, our observations contradict those assumptions: bound ligands occupy many conformational states, thereby stabilizing the complex, while also promoting protein flexibility.","PeriodicalId":90452,"journal":{"name":"Bioenergetics : open access","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2167-7662.1000145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35443793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Comparative Analysis of the Mitochondrial Physiology of Pancreatic β Cells. 胰腺β细胞线粒体生理学的比较分析。

Bioenergetics : open access Pub Date : 2014-03-01 DOI: 10.4172/2167-7662.1000110

Chul Kim, Pinal Patel, Lindsey M Gouvin, Melissa L Brown, Ahmed Khalil, Elizabeth M Henchey, Alejandro P Heuck, Nagendra Yadava

{"title":"Comparative Analysis of the Mitochondrial Physiology of Pancreatic β Cells.","authors":"Chul Kim, Pinal Patel, Lindsey M Gouvin, Melissa L Brown, Ahmed Khalil, Elizabeth M Henchey, Alejandro P Heuck, Nagendra Yadava","doi":"10.4172/2167-7662.1000110","DOIUrl":"https://doi.org/10.4172/2167-7662.1000110","url":null,"abstract":"The mitochondrial metabolism of β cells is thought to be highly specialized. Its direct comparison with other cells using isolated mitochondria is limited by the availability of islets/β cells in sufficient quantity. In this study, we have compared mitochondrial metabolism of INS1E/β cells with other cells in intact and permeabilized states. To selectively permeabilize the plasma membrane, we have evaluated the use of perfringolysin-O (PFO) in conjunction with microplate-based respirometry. PFO is a protein that binds membranes based on a threshold level of active cholesterol. Therefore, unless active cholesterol reaches a threshold level in mitochondria, they are expected to remain untouched by PFO. Cytochrome c sensitivity tests showed that in PFO-permeabilized cells, the mitochondrial integrity was completely preserved. Our data show that a time-dependent decline of the oligomycin-insensitive respiration observed in INS1E cells was due to a limitation in substrate supply to the respiratory chain. We predict that it is linked with the β cell-specific metabolism involving metabolites shuttling between the cytoplasm and mitochondria. In permeabilized β cells, the Complex l-dependent respiration was either transient or absent because of the inefficient TCA cycle. The TCA cycle insufficiency was confirmed by analysis of the CO2 evolution. This may be linked with lower levels of NAD+, which is required as a co-factor for CO2 producing reactions of the TCA cycle. β cells showed comparable OxPhos and respiratory capacities that were not affected by the inorganic phosphate (Pi) levels in the respiration medium. They showed lower ADP-stimulation of the respiration on different substrates. We believe that this study will significantly enhance our understanding of the β cell mitochondrial metabolism.","PeriodicalId":90452,"journal":{"name":"Bioenergetics : open access","volume":"3 1","pages":"110"},"PeriodicalIF":0.0,"publicationDate":"2014-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2167-7662.1000110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32742062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11