title: Molecular dynamics simulations reveal ligand-controlled positioning of a peripheral protein complex in membranes.
abstract: Bryostatin is in clinical trials for Alzheimer's disease, cancer, and HIV/AIDS eradication. It binds to protein kinase C competitively with diacylglycerol, the endogenous protein kinase C regulator, and plant-derived phorbol esters, but each ligand induces different activities. Determination of the structural origin for these differing activities by X-ray analysis has not succeeded due to difficulties in co-crystallizing protein kinase C with relevant ligands. More importantly, static, crystal-lattice bound complexes do not address the influence of the membrane on the structure and dynamics of membrane-associated proteins. To address this general problem, we performed long-timescale (400-500 µs aggregate) all-atom molecular dynamics simulations of protein kinase C-ligand-membrane complexes and observed that different protein kinase C activators differentially position the complex in the membrane due in part to their differing interactions with waters at the membrane inner leaf. These new findings enable new strategies for the design of simpler, more effective protein kinase C analogs and could also prove relevant to other peripheral protein complexes.Natural supplies of bryostatin, a compound in clinical trials for Alzheimer's disease, cancer, and HIV, are scarce. Here, the authors perform molecular dynamics simulations to understand how bryostatin interacts with membrane-bound protein kinase C, offering insights for the design of bryostatin analogs.
authors.affiliation: Departments of Chemistry and of Chemical & Systems Biology, Stanford University, Stanford, California, 94305, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Ryckbosch
authors.affiliation: Departments of Chemistry and of Chemical & Systems Biology, Stanford University, Stanford, California, 94305, USA. wenderp@Stanford.EDU.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
authors.affiliation: Departments of Chemistry and of Chemical & Systems Biology, Stanford University, Stanford, California, 94305, USA. pande@stanford.edu.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D054713:Bryostatins / Q000737:chemistry* / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010703:Phorbol Esters / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D054713:Bryostatins; D004075:Diglycerides; D008024:Ligands; D008565:Membrane Proteins; D010703:Phorbol Esters; D047428:Protein Kinase Inhibitors; D014867:Water; C046785:bryostatin 1; C070999:prostratin; D011493:Protein Kinase C